3-(ethoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine as an ion channel modulator

ABSTRACT

The present invention is directed to, in part, fused heteroaryl compounds, such as the compound: 
     
       
         
         
             
             
         
       
     
     and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2019/034653, with an international filing date of May 30, 2019,which claims priority to and the benefit of U.S. Provisional PatentApplication No. 62/677,903, filed May 30, 2018, and 62/738,508, filedSep. 28, 2018, each of which is incorporated herein by reference in itsentirety.

BACKGROUND

Sodium ion (Na+) channels primarily open in a transient manner and arequickly inactivated, thereby generating a fast Na+ current to initiatethe action potential. The late or persistent sodium current (INaL) is asustained component of the fast Na+ current of cardiac myocytes andneurons. Many common neurological and cardiac conditions are associatedwith abnormal INaL enhancement, which contributes to the pathogenesis ofboth electrical and contractile dysfunction in mammals (see, e.g.,Pharmacol Ther (2008) 119:326-339). Accordingly, pharmaceuticalcompounds that selectively modulate sodium channel activity, e.g.,abnormal INaL, are useful in treating such disease states.

SUMMARY

Described herein are fused heteroaryl compounds and compositions usefulfor preventing and/or treating a disease, disorder, or condition, e.g.,a disease, disorder, or condition relating to aberrant function of asodium ion channel, e.g., abnormal late sodium current (INaL). In oneaspect, the present disclosure features compounds of Formula (I):

In one aspect, the present invention provides a compound having theFormula I:

or a pharmaceutically acceptable salt thereof, wherein

X and Y are each independently CR^(d) or N;

R¹ is

monocyclic C₃₋₆ cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl,wherein said cycloalkyl and heterocyclyl are optionally substituted withone or more R^(a);

R² is C₁₋₄haloalkyl, phenyl, or monocyclic C₃₋₆ cycloalkyl optionallysubstituted with one or more R^(b);

R³ is hydrogen, C₁₋₄alkyl, or C₁₋₄haloalkyl;

R⁴ is hydrogen or C₁₋₄alkyl;

R⁵ is halo;

R⁶ is C₁₋₄alkyl or C₁₋₄haloalkyl, wherein said C₁₋₄alkyl orC₁₋₄haloalkyl are each substituted with OR^(c);

t is 0, 1, or 2;

R^(a) and R^(b) are each independently selected from is selected fromhalo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, and C₁₋₄haloalkoxy,

R^(c) is C₁₋₄alkyl optionally substituted with C₃₋₆ cycloalkyl orC₁₋₄alkoxy, or C₃₋₆ cycloalkyl; and

R^(d) is hydrogen or C₁₋₄alkyl;

provided the compound is not a compound having the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is of the Formula I-a:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula I-b:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula II:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula III:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula I-c:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In another aspect, the present disclosure provides a compound having theFormula I-d:

or a pharmaceutically acceptable salt thereof, wherein

R¹ is

monocyclic C₃₋₆ cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl,wherein said cycloalkyl and heterocyclyl are optionally substituted withone or more R^(a);

R² is C₁₋₄haloalkyl, phenyl, or monocyclic C₃₋₆ cycloalkyl optionallysubstituted with one or more R^(b);

R³ is hydrogen, C₁₋₄alkyl, or C₁₋₄haloalkyl;

R⁴ is hydrogen or C₁₋₄alkyl;

R⁵ is halo;

R⁶ is C₁₋₄alkyl or C₁₋₄haloalkyl, wherein said C₁₋₄alkyl orC₁₋₄haloalkyl are each substituted with OR^(c);

t is 0, 1, or 2;

R^(a) and R^(b) are each independently selected from is selected fromhalo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, and C₁₋₄haloalkoxy;

R^(c) is C₁₋₄alkyl optionally substituted with C₃₋₆ cycloalkyl orC₁₋₄alkoxy, or C₃₋₆ cycloalkyl; and

R^(d) is hydrogen or C₁₋₄alkyl.

In some embodiments, the compound is of the Formula V:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula VII:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In another aspect, provided herein is a crystalline compound of formula:

wherein the crystalline compound exhibits an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):6.9±0.2, 16.5±0.2, and 20.8±0.2.

In another aspect, provided herein is a crystalline compound of formula:

wherein the crystalline compound exhibits an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):16.7±0.2, 19.0±0.2, and 20.4±0.2.

In another aspect, the present invention provides a crystalline compoundof formula:

wherein the crystalline compound exhibits an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):7.3±0.2, 14.5±0.2, and 21.9±0.2.

In another aspect, the present disclosure provides a crystallinecompound of formula:

wherein the crystalline compound exhibits an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):12.6±0.2, 15.8±0.2, and 18.6±0.2.

In another aspect, the present invention provides a crystalline compoundof formula:

wherein the crystalline compound exhibits an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):5.8±0.2, 19.7±0.2, and 21.0±0.2.

In another aspect, the present invention provides a crystalline compoundof formula:

wherein the crystalline compound exhibits an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):7.3±0.2, 16.6±0.2, and 18.4±0.2.

In another aspect, the present invention provides a crystalline compoundof formula:

wherein the crystalline compound exhibits an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):6.9±0.2, 16.4±0.2, and 19.5±0.2.

In another aspect, the present invention provides a crystalline compoundof formula:

wherein the crystalline compound exhibits an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):9.9±0.2, 19.8±0.2, and 23.7±0.2.

In another aspect, the present disclosure provides a crystallinecompound of formula:

wherein the crystalline compound exhibits an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):9.3±0.2, 18.8±0.2, and 21.4±0.2.

In another aspect, provided herein is a pharmaceutical compositioncomprising a compound disclosed herein, or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier.

In another aspect of the disclosure, a composition comprising a compounddisclosed herein (e.g., a compound of Formula I, I′, I-a, I-b, I-c, I-d,II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier is provided.

Also provided herein is a pharmaceutical composition comprising acompound disclosed herein (e.g., a compound of Formula I, I′, I-a, I-b,I-c, I-d, II, III, V, VII, VIII, or IX), or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable carrier, foruse in medicine.

In another aspect, provided herein is a method of treating a conditionrelating to aberrant function of a sodium ion channel in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound disclosed herein (e.g., a compound of Formula I,I′, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX), or apharmaceutically acceptable salt thereof, or a composition or apharmaceutical composition disclosed herein.

In some embodiments, the condition is a neurological or psychiatricdisorder. In some embodiments, the condition is epilepsy or an epilepsysyndrome. In some embodiments, the condition is a genetic epilepsy or agenetic epilepsy syndrome. In some embodiments, the condition is apediatric epilepsy or a pediatric epilepsy syndrome. In someembodiments, the condition is epileptic encephalopathy. In someembodiments, the epileptic encephalopathy is selected from the groupconsisting of Dravet syndrome, infantile spasms, and Lennox-Gastautsyndrome.

In some embodiments, the condition is selected from the group consistingof epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A,SCN8A mutations, early infantile epileptic encephalopathy, Dravetsyndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy withfebrile seizures, intractable childhood epilepsy with generalizedtonic-clonic seizures, infantile spasms, benign familialneonatal-infantile seizures, SCN2A epileptic encephalopathy, focalepilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsywith SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpecteddeath in epilepsy, Rasmussen encephalitis, malignant migrating partialseizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy,sudden expected death in epilepsy (SUDEP), KCNQ2 epilepticencephalopathy, and KCNT1 epileptic encephalopathy.

In another aspect, provided herein is a method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compounddisclosed herein (e.g., a compound of Formula I, I′, I-a, I-b, I-c, I-d,II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable saltthereof or a composition or a pharmaceutical composition disclosedherein.

In another aspect, the present invention provides a method of treating apain, wherein the method comprises administering to a subject in needthereof a compound disclosed herein (e.g., a compound of Formula I, I′,I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX), or a pharmaceuticallyacceptable salt thereof or a composition or a pharmaceutical compositiondisclosed herein.

The present disclosure also provides a composition comprising a compounddisclosed herein (e.g., a compound of Formula I, I′, I-a, I-b, I-c, I-d,II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition disclosed herein, or acomposition disclosed herein for treating a condition relating toaberrant function of a sodium ion channel in a subject.

In some embodiments, the condition is a neurological or psychiatricdisorder. In some embodiments, the condition is a pain. In someembodiments, the condition is epilepsy or an epilepsy syndrome. In someembodiments, the condition is a genetic epilepsy or a genetic epilepsysyndrome. In some embodiments, the condition is a pediatric epilepsy ora pediatric epilepsy syndrome. In some embodiments, the condition isepileptic encephalopathy. In some embodiments, the epilepticencephalopathy is selected from the group consisting of Dravet syndrome,infantile spasms, and Lennox-Gastaut syndrome.

In some embodiments, the condition is selected from the group consistingof epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A,SCN8A mutations, early infantile epileptic encephalopathy, Dravetsyndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy withfebrile seizures, intractable childhood epilepsy with generalizedtonic-clonic seizures, infantile spasms, benign familialneonatal-infantile seizures, SCN2A epileptic encephalopathy, focalepilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsywith SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpecteddeath in epilepsy, Rasmussen encephalitis, malignant migrating partialseizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy,sudden expected death in epilepsy (SUDEP), KCNQ2 epilepticencephalopathy, and KCNT1 epileptic encephalopathy.

In another aspect, the present disclosure provides a compositioncomprising a compound disclosed herein (e.g., a compound of Formula I,I′, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX), or apharmaceutically acceptable salt thereof, a pharmaceutical compositiondisclosed herein, or a composition disclosed herein for treating aneurological disorder or a psychiatric disorder.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing Detailed Description,Examples, and Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows XRPD pattern of Compound 10 raw material.

FIG. 1B shows DSC of Compound 10.

FIG. 2A shows XRPD pattern of Compound 62 raw material.

FIG. 2B shows DSC of Compound 62.

FIG. 3A shows XRPD pattern of Compound 6B raw material.

FIG. 3B shows DSC of Compound 6B.

FIG. 4A shows XRPD pattern of Compound 56 raw material.

FIG. 4B shows DSC of Compound 56.

FIG. 5A shows XRPD pattern of Compound 3 raw material.

FIG. 5B shows DSC of Compound 3.

FIG. 6A shows XRPD pattern of Compound 11 raw material.

FIG. 6B shows DSC of Compound 11.

FIG. 7A shows XRPD pattern of Compound 53 raw material.

FIG. 7B shows DSC of Compound 53.

FIG. 8A shows XRPD pattern of Compound 59 raw material.

FIG. 8B shows DSC of Compound 59.

FIG. 9A shows XRPD pattern of Compound 48 raw material.

FIG. 9B shows DSC of Compound 48.

DETAILED DESCRIPTION

As generally described herein, the present invention provides compoundsand compositions useful for preventing and/or treating a disease,disorder, or condition described herein, e.g., a disease, disorder, orcondition relating to aberrant function of a sodium ion channel, such asabnormal late sodium current (INaL). Exemplary diseases, disorders, orconditions include a neurological disorder (e.g., epilepsy or anepilepsy syndrome, a neurodevelopmental disorder or a neuromusculardisorder), a psychiatric disorder, pain, or a gastrointestinal disorder.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5th Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pure R-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure R-compound. In certain embodiments, theenantiomerically pure R-compound in such compositions can, for example,comprise, at least about 95% by weight R-compound and at most about 5%by weight S-compound, by total weight of the compound. For example, apharmaceutical composition comprising enantiomerically pure S-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

Compound described herein may also comprise one or more isotopicsubstitutions. For example, H may be in any isotopic form, including ¹H,²H (D or deuterium), and ³H (T or tritium); C may be in any isotopicform, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form,including ¹⁶O and ¹⁸O; F may be in any isotopic form, including ¹⁸F and¹⁹F; and the like.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention. When describing the invention,which may include compounds and pharmaceutically acceptable saltsthereof, pharmaceutical compositions containing such compounds andmethods of using such compounds and compositions, the following terms,if present, have the following meanings unless otherwise indicated. Itshould also be understood that when described herein any of the moietiesdefined forth below may be substituted with a variety of substituents,and that the respective definitions are intended to include suchsubstituted moieties within their scope as set out below. Unlessotherwise stated, the term “substituted” is to be defined as set outbelow. It should be further understood that the terms “groups” and“radicals” can be considered interchangeable when used herein. Thearticles “a” and “an” may be used herein to refer to one or to more thanone (i.e. at least one) of the grammatical objects of the article. Byway of example “an analogue” means one analogue or more than oneanalogue.

When a range of values is listed, it is intended to encompass each valueand subrange within the range. For example, “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, “alkyl” refers to a radical of a straight-chain orbranched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms(“C₁₋₂₀ alkyl”). In some embodiments, an alkyl group has 1 to 10 carbonatoms (“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9carbon atoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1to 8 carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl grouphas 1 to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkylgroup has 1 to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, analkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments,an alkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In someembodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). Insome embodiments, an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”).In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”).Examples of C₁₋₆ alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, pentyl, hexyl, and the like.

As used herein, “alkenyl” refers to a radical of a straight-chain orbranched hydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2 propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂-6 alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like.

As used herein, “alkynyl” refers to a radical of a straight-chain orbranched hydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1 butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂), 1propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and thelike. Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and the like.Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), andthe like.

As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to adivalent radical of an alkyl, alkenyl, and alkynyl group respectively.When a range or number of carbons is provided for a particular“alkylene,” “alkenylene,” or “alkynylene,” group, it is understood thatthe range or number refers to the range or number of carbons in thelinear carbon divalent chain. “Alkylene,” “alkenylene,” and“alkynylene,” groups may be substituted or unsubstituted with one ormore substituents as described herein.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has six ring carbon atoms(“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has tenring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has fourteen ring carbonatoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systemswherein the aryl ring, as defined above, is fused with one or morecarbocyclyl or heterocyclyl groups wherein the radical or point ofattachment is on the aryl ring, and in such instances, the number ofcarbon atoms continue to designate the number of carbon atoms in thearyl ring system. Typical aryl groups include, but are not limited to,groups derived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, and trinaphthalene. Particularly aryl groups includephenyl, naphthyl, indenyl, and tetrahydronaphthyl.

As used herein, “heteroaryl” refers to a radical of a 5-10 -memberedmonocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10electrons shared in a cyclic array) having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 -membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 -membered aromaticring system having ring carbon atoms and 1-4 ring heteroatoms providedin the aromatic ring system, wherein each heteroatom is independentlyselected from nitrogen, oxygen, and sulfur (“5-10 -memberedheteroaryl”). In some embodiments, a heteroaryl group is a 5-8 -memberedaromatic ring system having ring carbon atoms and 1-4 ring heteroatomsprovided in the aromatic ring system, wherein each heteroatom isindependently selected from nitrogen, oxygen, and sulfur (“5-8 -memberedheteroaryl”). In some embodiments, a heteroaryl group is a 5-6 -memberedaromatic ring system having ring carbon atoms and 1-4 ring heteroatomsprovided in the aromatic ring system, wherein each heteroatom isindependently selected from nitrogen, oxygen, and sulfur (“5-6 -memberedheteroaryl”). In some embodiments, the 5-6 -membered heteroaryl has 1-3ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 -membered heteroaryl has 1-2 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl has 1 ring heteroatom selected from nitrogen,oxygen, and sulfur.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁₋₈ alkyl, C₃₋₁₀ carbocyclyl, 4-10 -memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of anon aromatic cyclic hydrocarbon group having from 3 to 10 ring carbonatoms (“C₃₋₁₀ carbocyclyl”) and zero heteroatoms in the nonaromatic ringsystem. In some embodiments, a carbocyclyl group has 3 to 8 ring carbonatoms (“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has3 to 7 ring carbon atoms (“C₃₋₇ carbocycyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclobutyl (C₄), cyclobutenyl(C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆),cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C₃₋₈carbocyclyl groups include, without limitation, the aforementioned C₃₋₆carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈),cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl(C₈), and the like. Exemplary C₃₋₁₀ carbocyclyl groups include, withoutlimitation, the aforementioned C₃₋₈ carbocyclyl groups as well ascyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl(C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀),spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic,or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8,or 4-6 carbons, referred to herein, e.g., as “C₄₋₈cycloalkyl,” derivedfrom a cycloalkane. Exemplary cycloalkyl groups include, but are notlimited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.

As used herein, “C₃₋₆ monocyclic cycloalkyl” or “monocyclic C₃₋₆cycloalkyl” refers to a 3- to 7-membered monocyclic hydrocarbon ringsystem that is saturated. 3- to 7-membered monocyclic cycloalkyl groupsinclude, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. Where specified as being optionally substituted orsubstituted, substituents on a cycloalkyl (e.g., in the case of anoptionally substituted cycloalkyl) may be present on any substitutableposition and, include, e.g., the position at which the cycloalkyl groupis attached.

As used herein, “heterocyclyl” or “heterocyclic” refers to a radical ofa 3 to 10-membered nonaromatic ring system having ring carbon atoms and1 to 4 ring heteroatoms, wherein each heteroatom is independentlyselected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon(“3-10 -membered heterocyclyl”). In heterocyclyl groups that contain oneor more nitrogen atoms, the point of attachment can be a carbon ornitrogen atom, as valency permits. A heterocyclyl group can either bemonocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ringsystem such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. The terms “heterocycle,”“heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclicmoiety,” and “heterocyclic radical,” may be used interchangeably.

In some embodiments, a heterocyclyl group is a 4-7 -memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“4-7 -membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-10 -membered nonaromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, sulfur,boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 -membered nonaromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 -membered heterocyclyl”). In some embodiments, a heterocyclylgroup is a 5-6 -membered nonaromatic ring system having ring carbonatoms and 1-4 ring heteroatoms, wherein each heteroatom is independentlyselected from nitrogen, oxygen, and sulfur (“5-6 -memberedheterocyclyl”). In some embodiments, the 5-6 -membered heterocyclyl has1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 -membered heterocyclyl has 1-2 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has one ring heteroatom selected from nitrogen,oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8membered heterocyclyl groups containing one heteroatom include, withoutlimitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-memberedheterocyclyl groups fused to a C₆ aryl ring (also referred to herein asa 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

Examples of saturated or partially unsaturated heterocyclic radicalsinclude, without limitation, tetrahydrofuranyl, tetrahydrothienyl,terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl,dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl.Where specified as being optionally substituted or substituted,substituents on a heterocyclyl (e.g., in the case of an optionallysubstituted heterocyclyl) may be present on any substitutable positionand, include, e.g., the position at which the heterocyclyl group isattached.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g,heteroaryl; and the like having from 1 to 5, and particularly from 1 to3 heteroatoms.

As used herein, “cyano” refers to —CN.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), and iodine (iodo, —I). In certain embodiments, the halo group iseither fluoro or chloro.

The term “alkoxy,” as used herein, refers to an alkyl group which isattached to another moiety via an oxygen atom (—O(alkyl)). Non-limitingexamples include e.g., methoxy, ethoxy, propoxy, and butoxy.

“Haloalkoxy” is a haloalkyl group which is attached to another moietyvia an oxygen atom such as, e.g., but are not limited to —OCHCF₂ or—OCF₃.

The term “haloalkyl” includes mono, poly, and perhaloalkyl groupssubstituted with one or more halogen atoms where the halogens areindependently selected from fluorine, chlorine, bromine, and iodine. Forthe group C₁₋₄haloalkyl-O—C₁₋₄alkyl, the point of attachment occurs onthe alkyl moiety which is halogenated.

As used herein, “nitro” refers to —NO₂.

As used herein, “oxo” refers to —C═O.

In general, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group(e.g., a carbon or nitrogen atom) is replaced with a permissiblesubstituent, e.g., a substituent which upon substitution results in astable compound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(—NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 -membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 -memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 -membered heterocyclyl or 5-14 -membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), bb, R^(cc) and R^(dd) are as definedabove.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

As used herein, “pharmaceutically acceptable carrier” refers to anon-toxic carrier, adjuvant, or vehicle that does not destroy thepharmacological activity of the compound with which it is formulated.Pharmaceutically acceptable carriers, adjuvants or vehicles that may beused in the compositions described herein include, but are not limitedto, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

As used herein, “pharmaceutically acceptable salt” refers to those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, ptoluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

As used herein, a “subject” to which administration is contemplatedincludes, but is not limited to, humans (i.e., a male or female of anyage group, e.g., a pediatric subject (e.g, infant, child, adolescent) oradult subject (e.g., young adult, middle-aged adult or senior adult))and/or a non-human animal, e.g., a mammal such as primates (e.g.,cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats,rodents, cats, and/or dogs. In certain embodiments, the subject is ahuman. In certain embodiments, the subject is a non-human animal. Theterms “human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

As used herein, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

Compounds

In one aspect, the present invention provides a compound having theFormula I:

or a pharmaceutically acceptable salt thereof, wherein

-   -   X and Y are each independently CR^(d) or N;    -   R¹ is

monocyclic C₃₋₆ cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl,wherein said cycloalkyl and heterocyclyl are optionally substituted withone or more R^(a);

-   -   R² is C₁₋₄haloalkyl, phenyl, or monocyclic C₃₋₆ cycloalkyl        optionally substituted with one or more R^(b);    -   R³ is hydrogen, C₁₋₄alkyl, or C₁₋₄haloalkyl;    -   R⁴ is hydrogen or C₁₋₄alkyl;    -   R⁵ is halo;    -   R⁶ is C₁₋₄alkyl or C₁₋₄haloalkyl, wherein said C₁₋₄alkyl or        C₁₋₄haloalkyl are each substituted with OR^(c);    -   t is 0, 1, or 2;    -   R^(a) and R^(b) are each independently selected from is selected        from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, and        C₁₋₄haloalkoxy,    -   R^(c) is C₁₋₄alkyl optionally substituted with C₃₋₆ cycloalkyl        or C₁₋₄alkoxy, or C₃₋₆ cycloalkyl; and    -   R^(d) is hydrogen or C₁₋₄alkyl;    -   provided the compound is not a compound having the formula:

or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides a compound having theFormula I′:

or a pharmaceutically acceptable salt thereof, wherein

-   -   X and Y are each independently CR^(d) or N;    -   R¹ is

monocyclic C₃₋₆ cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl,wherein said cycloalkyl and heterocyclyl are optionally substituted withone or more R^(a);

-   -   R² is C₁₋₄haloalkyl, phenyl, or monocyclic C₃₋₆ cycloalkyl        optionally substituted with one or more R^(b);    -   R³ is hydrogen, C₁₋₄alkyl, or C₁₋₄haloalkyl;    -   R⁴ is hydrogen or C₁₋₄alkyl;    -   R⁵ is halo;    -   R⁶ is C₁₋₄alkyl or C₁₋₄haloalkyl, wherein said C₁₋₄alkyl or        C₁₋₄haloalkyl are each substituted with OR^(c);    -   t is 0, 1, or 2;    -   R^(a) and R^(b) are each independently selected from is selected        from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, and        C₁₋₄haloalkoxy,    -   R^(c) is C₁₋₄alkyl optionally substituted with C₃₋₆ cycloalkyl        or C₁₋₄alkoxy, or C₃₋₆ cycloalkyl; and    -   R^(d) is hydrogen or C₁₋₄alkyl;        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is of the Formula I-a:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula I-b:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula II:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula III:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula I-c:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In another aspect, the present disclosure provides a compound having theFormula I-d:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is

monocyclic C₃₋₆ cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl,wherein said cycloalkyl and heterocyclyl are optionally substituted withone or more R^(a);

-   -   R² is C₁₋₄haloalkyl, phenyl, or monocyclic C₃₋₆ cycloalkyl        optionally substituted with one or more R^(b);    -   R³ is hydrogen, C₁₋₄alkyl, or C₁₋₄haloalkyl;    -   R⁴ is hydrogen or C₁₋₄alkyl;    -   R⁵ is halo;    -   R⁶ is C₁₋₄alkyl or C₁₋₄haloalkyl, wherein said C₁₋₄alkyl or        C₁₋₄haloalkyl are each substituted with OR^(c);    -   t is 0, 1, or 2;    -   R^(a) and R^(b) are each independently selected from is selected        from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, and        C₁₋₄haloalkoxy;    -   R^(c) is C₁₋₄alkyl optionally substituted with C₃₋₆ cycloalkyl        or C₁₋₄alkoxy, or C₃₋₆ cycloalkyl; and    -   R^(d) is hydrogen or C₁₋₄alkyl.

In some embodiments, the compound is of the Formula V:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula VII:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is of the Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, R¹ is

In some embodiments, R² is cyclobutyl optionally substituted with one ormore R^(a).

In some embodiments, R² is C₁₋₄haloalkyl. In some embodiments, R² isCF₃. In some embodiments, R² is phenyl.

In some embodiments, R³ is C₁₋₄alkyl and R⁴ is hydrogen or C₁₋₄alkyl. Insome embodiments, R³ and R⁴ are each C₁₋₄alkyl. In some embodiments, R³and R⁴ are each methyl. In some embodiments, R³ is methyl and R⁴ ishydrogen. In some embodiments, R³ and R⁴ are each hydrogen.

In some embodiments, R⁶ is —CF₂—OR^(c).

In some embodiments, R^(c) is C₁₋₄alkyl optionally substituted withcyclopropyl. In some embodiments, R^(c) is cyclopropyl.

In some embodiments, R⁶ is —C(F₂)OCH₂CH(CH₃)₂, —C(F₂)OCH₃,—C(F₂)OCH₂CH₃, —C(F₂)OCH(CH₃)₂, or —C(F₂)OCH₂C₃H₅.

In some embodiments, R⁶ is —CH₂—OR^(c).

In some embodiments, R^(c) is C₁₋₄ alkyl.

In some embodiments, R⁶ is —CH₂OCH₃, —CH₂OCH₂CH₃, or —CH₂OCH₂CH(CH₃)₂.

In some embodiments, R^(a) is C₁₋₄haloalkyl. In some embodiments, R^(a)is CF₃. In some embodiments, R^(a) is fluoro.

In some embodiments, t is 1. In some embodiments, t is 0.

In some embodiments, R^(d) is methyl. In some embodiments, R^(d) ishydrogen.

In some embodiments, the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a crystalline compoundof formula:

-   -   wherein the crystalline compound exhibits an X-ray powder        diffraction pattern comprising peaks at the following        diffraction angles (2θ): 6.9±0.2, 16.5±0.2, and 20.8±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 6.9±0.2, 13.9±0.2, 16.5±0.2, 19.5±0.2, and 20.8±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 6.9±0.2, 11.2±0.2, 13.9±0.2, 16.5±0.2, 17.4±0.2, 18.1±0.2,19.1±0.2, 19.5±0.2, and 20.8±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern substantially the same as depicted in FIG. 2A.

In some embodiments, the crystalline compound has a melting point onsetas determined by differential scanning calorimetry at about 140° C.

In some embodiments, the crystalline compound has a differentialscanning calorimetry curve substantially the same as shown in FIG. 2B.

In another aspect, provided herein is a crystalline compound of formula:

-   -   wherein the crystalline compound exhibits an X-ray powder        diffraction pattern comprising peaks at the following        diffraction angles (2θ): 16.7±0.2, 19.0±0.2, and 20.4±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 7.2±0.2, 14.4±0.2, 16.7±0.2, 19.0±0.2, 20.4±0.2, and 25.7±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 7.2±0.2, 14.4±0.2, 16.7±0.2, 17.9±0.2, 19.0±0.2, 20.4±0.2,20.8±0.2, 23.2±0.2, 25.7±0.2, and 28.0±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern substantially the same as depicted in FIG. 3A.

In some embodiments, the crystalline compound has a melting point onsetas determined by differential scanning calorimetry at about 68° C.

In some embodiments, the crystalline compound has a differentialscanning calorimetry curve substantially the same as shown in FIG. 3B.

In another aspect, the present invention provides a crystalline compoundof formula:

-   -   wherein the crystalline compound exhibits an X-ray powder        diffraction pattern comprising peaks at the following        diffraction angles (2θ): 7.3±0.2, 14.5±0.2, and 21.9±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 7.3±0.2, 14.5±0.2, 17.9±0.2, 19.0±0.2, and 21.9±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 7.3±0.2, 13.7±0.2, 14.5±0.2, 17.9±0.2, 19.0±0.2, 20.3±0.2,21.9±0.2, 24.7±0.2, and 25.4±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern substantially the same as depicted in FIG. 4A.

In some embodiments, the crystalline compound has a melting point onsetas determined by differential scanning calorimetry at about 136° C.

In some embodiments, the crystalline compound has a differentialscanning calorimetry curve substantially the same as shown in FIG. 4B.

In another aspect, provided herein is a crystalline compound of formula:

-   -   wherein the crystalline compound exhibits an X-ray powder        diffraction pattern comprising peaks at the following        diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2,16.8±0.2, 18.6±0.2, 21.0±0.2 and 22.6±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern substantially the same as depicted in FIG. 5A.

In some embodiments, the crystalline compound has a melting point onsetas determined by differential scanning calorimetry at about 107° C.

In some embodiments, the crystalline compound has a differentialscanning calorimetry curve substantially the same as shown in FIG. 5B.

In another aspect, provided herein is a crystalline compound of formula:

-   -   wherein the crystalline compound exhibits an X-ray powder        diffraction pattern comprising peaks at the following        diffraction angles (2θ): 5.8±0.2, 19.7±0.2, and 21.0±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 5.8±0.2, 14.5±0.2, 15.3±0.2, 19.7±0.2, 21.0±0.2, and 24.2±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 5.8±0.2, 11.6±0.2, 12.0±0.2, 14.5±0.2, 15.3±0.2, 19.1±0.2,19.7±0.2, 21.0±0.2, 22.4±0.2, and 24.2±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern substantially the same as depicted in FIG. 6A.

In some embodiments, the crystalline compound has a melting point onsetas determined by differential scanning calorimetry at about 94° C.

In some embodiments, the crystalline compound has a differentialscanning calorimetry curve substantially the same as shown in FIG. 6B.

In another aspect, the present invention provides a crystalline compoundof formula:

-   -   wherein the crystalline compound exhibits an X-ray powder        diffraction pattern comprising peaks at the following        diffraction angles (2θ): 7.3±0.2, 16.6±0.2, and 18.4±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 7.3±0.2, 13.8±0.2, 16.6±0.2, 18.4±0.2, 20.3±0.2, and 24.3±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 7.3±0.2, 10.8±0.2, 13.8±0.2, 16.6±0.2, 17.8±0.2, 18.4±0.2,19.5±0.2, 20.3±0.2, 21.2±0.2, and 24.3±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern substantially the same as depicted in FIG. 7A.

In some embodiments, the crystalline compound has a melting point onsetas determined by differential scanning calorimetry at about 103° C.

In some embodiments, the crystalline compound has a differentialscanning calorimetry curve substantially the same as shown in FIG. 7B.

In another aspect, the present invention provides a crystalline compoundof formula:

-   -   wherein the crystalline compound exhibits an X-ray powder        diffraction pattern comprising peaks at the following        diffraction angles (2θ): 6.9±0.2, 16.4±0.2, and 19.5±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 6.9±0.2, 16.4±0.2, 17.4±0.2, 18.0±0.2, 19.5±0.2, and 20.8±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 6.9±0.2, 11.2±0.2, 13.6±0.2, 13.9±0.2, 16.4±0.2, 17.4±0.2,18.0±0.2, 19.5±0.2, and 20.8±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern substantially the same as depicted in FIG. 8A.

In some embodiments, the crystalline compound has a melting point onsetas determined by differential scanning calorimetry at about 133° C.

In some embodiments, the crystalline compound has a differentialscanning calorimetry curve substantially the same as shown in FIG. 8B.

In another aspect, the present disclosure provides a crystallinecompound of formula:

-   -   wherein the crystalline compound exhibits an X-ray powder        diffraction pattern comprising peaks at the following        diffraction angles (2θ): 9.9±0.2, 19.8±0.2, and 23.7±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 9.9±0.2, 12.3±0.2, 14.1±0.2, 19.8±0.2, 20.7±0.2, and 23.7±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 7.3±0.2, 9.9±0.2, 12.3±0.2, 14.1±0.2, 16.5±0.2, 17.2±0.2,19.8±0.2, 20.7±0.2, 23.7±0.2, 24.8±0.2, 27.7±0.2, and 29.1±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern substantially the same as depicted in FIG. 9A.

In some embodiments, the crystalline compound has a melting point onsetas determined by differential scanning calorimetry at about 111° C.

In some embodiments, the crystalline compound has a differentialscanning calorimetry curve substantially the same as shown in FIG. 9B.

In another aspect, provided herein is a crystalline compound of formula:

-   -   wherein the crystalline compound exhibits an X-ray powder        diffraction pattern comprising peaks at the following        diffraction angles (2θ): 9.3±0.2, 18.8±0.2, and 21.4±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, and 21.6±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, 21.6±0.2,22.6±0.2, 23.9±0.2, 26.0±0.2, and 26.4±0.2.

In some embodiments, the crystalline compound exhibits an X-ray powderdiffraction pattern substantially the same as depicted in FIG. 1A.

In some embodiments, the crystalline compound has a melting point onsetas determined by differential scanning calorimetry at about 122° C.

In some embodiments, the crystalline compound has a differentialscanning calorimetry curve substantially the same as shown in FIG. 1B.

In some embodiments, the X-ray powder diffraction pattern was obtainedusing Cu Kα radiation.

Pharmaceutical Compositions and Routes of Administration

Compounds provided in accordance with the present invention are usuallyadministered in the form of pharmaceutical compositions. This inventiontherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present invention in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral administration is another route for administration of compounds inaccordance with the invention. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g of a compound described herein, and for parenteraladministration, preferably from 0.1 to 700 mg of a compound a compounddescribed herein. It will be understood, however, that the amount of thecompound actually administered usually will be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompound administered and its relative activity, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

In some embodiments, a pharmaceutical composition comprising a disclosedcompound, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

Methods of Use

Compounds and compositions described herein are generally useful for themodulating the activity of sodium channels and are useful in treatingconditions relating to aberrant function of a sodium channel ionchannel, e.g., abnormal late sodium (INaL) current. In some embodiments,a compound provided by the present invention is effective in thetreatment of epilepsy or an epilepsy syndrome, a neurodevelopmentaldisorder, pain, or a neuromuscular disorder. A provided compound,pharmaceutically acceptable salt thereof, or composition may alsomodulate all sodium ion channels, or may be specific to only one or aplurality of sodium ion channels, e.g., Nay 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, and/or 1.9.

In typical embodiments, the present invention is intended to encompassthe compounds disclosed herein, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, tautomeric forms, polymorphs,and prodrugs of such compounds. In some embodiments, the presentinvention includes a pharmaceutically acceptable addition salt, apharmaceutically acceptable ester, a solvate (e.g., hydrate) of anaddition salt, a tautomeric form, a polymorph, an enantiomer, a mixtureof enantiomers, a stereoisomer or mixture of stereoisomers (pure or as aracemic or non-racemic mixture) of a compound described herein, e.g. acompound of Formula I, I′, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, orIX); such as a compound of Formula named herein.

Epilepsy and Epilepsy Syndromes

The compounds described herein are useful in the treatment of epilepsyand epilepsy syndromes. Epilepsy is a CNS disorder in which nerve cellactivity in the brain becomes disrupted, causing seizures or periods ofunusual behavior, sensations and sometimes loss of consciousness.Seizure symptoms will vary widely, from a simple blank stare for a fewseconds to repeated twitching of their arms or legs during a seizure.

Epilepsy may involve a generalized seizure or a partial or focalseizure. All areas of the brain are involved in a generalized seizure. Aperson experiencing a generalized seizure may cry out or make somesound, stiffen for several seconds to a minute a then have rhythmicmovements of the arms and legs. The eyes are generally open, the personmay appear not to be breathing and may actually turn blue. The return toconsciousness is gradual and the person maybe confused from minutes tohours. There are six main types of generalized seizures: tonic-clonic,tonic, clonic, myoclonic, absence, and atonic seizures. In a partial orfocal seizure, only part of the brain is involved, so only part of thebody is affected. Depending on the part of the brain having abnormalelectrical activity, symptoms may vary.

Epilepsy, as described herein, includes a generalized, partial, complexpartial, tonic clonic, clonic, tonic, refractory seizures, statusepilepticus, absence seizures, febrile seizures, or temporal lobeepilepsy.

The compounds described herein (e.g., a compound of Formula I, I′, I-a,I-b, I-c, I-d, II, III, V, VII, VIII, or IX) may also be useful in thetreatment of epilepsy syndromes. Severe syndromes with diffuse braindysfunction caused, at least partly, by some aspect of epilepsy, arealso referred to as epileptic encephalopathies. These are associatedwith frequent seizures that are resistant to treatment and severecognitive dysfunction, for instance West syndrome.

In some embodiments, the epilepsy syndrome comprises an epilepticencephalopathy, such as Dravet syndrome, Angelman syndrome, CDKL5disorder, frontal lobe epilepsy, infantile spasms, West's syndrome,Juvenile Myoclonic Epilepsy, Landau-Kleffner syndrome, Lennox-Gastautsyndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

In some embodiments, the epilepsy or epilepsy syndrome is a geneticepilepsy or a genetic epilepsy syndrome. In some embodiments, epilepsyor an epilepsy syndrome comprises epileptic encephalopathy, epilepticencephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantileepileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1Amutation, generalized epilepsy with febrile seizures, intractablechildhood epilepsy with generalized tonic-clonic seizures, infantilespasms, benign familial neonatal-infantile seizures, SCN2A epilepticencephalopathy, focal epilepsy with SCN3A mutation, cryptogenicpediatric partial epilepsy with SCN3A mutation, SCN8A epilepticencephalopathy, sudden unexpected death in epilepsy, Rasmussenencephalitis, malignant migrating partial seizures of infancy, autosomaldominant nocturnal frontal lobe epilepsy, sudden expected death inepilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epilepticencephalopathy.

In some embodiments, the methods described herein further compriseidentifying a subject having epilepsy or an epilepsy syndrome (e.g.,epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A,SCN8A mutations, early infantile epileptic encephalopathy, Dravetsyndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy withfebrile seizures, intractable childhood epilepsy with generalizedtonic-clonic seizures, infantile spasms, benign familialneonatal-infantile seizures, SCN2A epileptic encephalopathy, focalepilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsywith SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpecteddeath in epilepsy, Rasmussen encephalitis, malignant migrating partialseizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy,sudden unexpected death in epilepsy (SUDEP), KCNQ2 epilepticencephalopathy, or KCNT1 epileptic encephalopathy) prior toadministration of a compound described herein (e.g., a compound ofFormula I, I′, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX).

In one aspect, the present invention features a method of treatingepilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy,epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, earlyinfantile epileptic encephalopathy, Dravet syndrome, Dravet syndromewith SCN1A mutation, generalized Epilepsy with febrile seizures,intractable childhood epilepsy with generalized tonic-clonic seizures,infantile spasms, benign familial neonatal-infantile seizures, SCN2Aepileptic encephalopathy, focal epilepsy with SCN3A mutation,cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8Aepileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussenencephalitis, malignant migrating partial seizures of infancy, autosomaldominant nocturnal frontal lobe epilepsy, sudden expected death inepilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epilepticencephalopathy) comprising administering to a subject in need thereof acompound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

A compound of the present invention (e.g., a compound of Formula I, I′,I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX) may also be used totreat an epileptic encephalopathy, wherein the subject has a mutation inone or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2,CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A,EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B,HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7,LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2,PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1,SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2,ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

In some embodiments, the methods described herein further compriseidentifying a subject having a mutation in one or more of ALDH7A1,ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8,CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3,GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2,KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1,PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2,SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22,SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B,STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX prior to administrationof a compound described herein (e.g., a compound of Formula I, I′, I-a,I-b, I-c, I-d, II, III, V, VII, VIII, or IX).

Neurodevelopmental Disorders

The compounds described herein may be useful in the treatment of aneurodevelopmental disorder. In some embodiments, the neurodevelopmentaldisorder comprises autism, autism with epilepsy, tuberous sclerosis,Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome,22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacialsyndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorderwith epilepsy. In some embodiments, the methods described herein furthercomprise identifying a subject having a neurodevelopmental disorder(e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile Xsyndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome,Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder withepilepsy) prior to administration of a compound described herein (e.g.,a compound of Formula I, I′, I-a, I-b, I-c, I-d, II, III, V, VII, VIII,or IX).

In one aspect, the present invention features a method of treating aneurodevelopmental disorder (e.g., autism, autism with epilepsy,tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelmansyndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willisyndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or aneurodevelopmental disorder with epilepsy) comprising administering to asubject in need thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.Pain

The compounds described herein may be useful in the treatment of pain.In some embodiments, the pain comprises neuropathic pain, trigeminalneuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine,familial hemiplegic migraine type 3, cluster headache, trigeminalneuralgia, cerebellar ataxia, or a related headache disorder. In someembodiments, the methods described herein further comprise identifying asubject having pain (e.g., neuropathic pain, trigeminal neuralgia,migraine, hemiplegic migraine, familial hemiplegic migraine, familialhemiplegic migraine type 3, cluster headache, trigeminal neuralgia,cerebellar ataxia, or a related headache disorder) prior toadministration of a compound described herein (e.g., a compound ofFormula I, I′, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX).

In one aspect, the present invention features a method of treating pain(e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegicmigraine, familial hemiplegic migraine, familial hemiplegic migrainetype 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or arelated headache disorder) comprising administering to a subject in needthereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.Neuromuscular Disorders

The compounds described herein may be useful in the treatment of aneuromuscular disorder. In some embodiments, the neuromuscular disordercomprises amyotrophic lateral sclerosis, multiple sclerosism, myotonia,paramyotonia congenita, potassium-aggravated myotonia, periodicparalysis, hyperkalemic periodic paralysis, hypokalemic periodicparalysis, or laryngospasm with SCN4A mutation. In some embodiments, themethods described herein further comprise identifying a subject having aneuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiplesclerosism, myotonia, paramyotonia congenita, potassium-aggravatedmyotonia, periodic paralysis, hyperkalemic periodic paralysis,hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation)prior to administration of a compound described herein (e.g., a compoundof Formula I, I′, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX).

In one aspect, the present invention features a method of treating aneuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiplesclerosism, myotonia, paramyotonia congenita, potassium-aggravatedmyotonia, periodic paralysis, hyperkalemic periodic paralysis,hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation)comprising administering to a subject in need thereof a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.Other Disorders

In some embodiments, a compound of the present invention (e.g., acompound of Formula I, I′, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, orIX) may have appropriate pharmacokinetic properties such that they maybe active with regard to the central and/or peripheral nervous system.In some embodiments, the compounds provided herein are used to treat acardiovascular disease such as atrial and ventricular arrhythmias,including atrial fibrillation, Prinzmetal's (variant) angina, stableangina, unstable angina, ischemia and reperfusion injury in cardiac,kidney, liver and the brain, exercise induced angina, pulmonaryhypertension, congestive heart disease including diastolic and systolicheart failure, recurrent ischemia, cerebral ischemia, stroke, renalischemia, ischemia associated with organ transplant, acute coronarysyndrome, peripheral arterial disease, intermittent claudication, andmyocardial infarction. In some embodiments, the compounds providedherein may be used in the treatment of diseases affecting theneuromuscular system resulting in itching, seizures, or paralysis, or inthe treatment of diabetes or reduced insulin sensitivity, and diseasestates related to diabetes, such as diabetic peripheral neuropathy. Insome embodiments, a disclosed method comprises administering thepharmaceutical composition.

In some embodiments, provided herein is a method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compounddisclosed herein, or a pharmaceutically acceptable salt thereof or apharmaceutical composition disclosed herein.

Combination Therapy

A compound or composition described herein (e.g., for use in modulatinga sodium ion channel, e.g., the late sodium (INaL) current) may beadministered in combination with another agent or therapy. A subject tobe administered a compound disclosed herein may have a disease,disorder, or condition, or a symptom thereof, that would benefit fromtreatment with another agent or therapy. These diseases or conditionscan relate to epilepsy or an epilepsy syndrome, a neurodevelopmentaldisorder, pain, or a neuromuscular disorder.

Antiepilepsy Agents

Anti-epilepsy agents include brivaracetam, carbamazepine, clobazam,clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide,ezogabine, felbamate, gabapentin, lacosamide, lamotrigine,levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital,phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate,valproic acid, vigabatrin, zonisamide, and cannabidiol.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from acombination treatment of the sodium channel blockers of the inventionwith other therapeutic agents include, without limitation, anginaincluding stable angina, unstable angina (UA), exercised-induced angina,variant angina, arrhythmias, intermittent claudication, myocardialinfarction including non-STE myocardial infarction (NSTEMI), pulmonaryhypertension including pulmonary arterial hypertension, heart failureincluding congestive (or chronic) heart failure and diastolic heartfailure and heart failure with preserved ejection fraction (diastolicdysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseasesor conditions include anti-anginals, heart failure agents,antithrombotic agents, antiarrhythmic agents, antihypertensive agents,and lipid lowering agents.

The co-administration of the sodium channel blockers of the inventionwith therapeutic agents suitable for treating cardiovascular relatedconditions allows enhancement in the standard of care therapy thepatient is currently receiving.

Anti-Anginals

Anti-anginals include beta-blockers, calcium channel blockers, andnitrates. Beta blockers reduce the heart's need for oxygen by reducingits workload resulting in a decreased heart rate and less vigorous heartcontraction. Examples of beta-blockers include acebutolol (Sectral),atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide(Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc),labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL),nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), andtimolol (Blocadren).

Nitrates dilate the arteries and veins thereby increasing coronary bloodflow and decreasing blood pressure. Examples of nitrates includenitroglycerin, nitrate patches, isosorbide dinitrate, andisosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into thecells of the heart and blood vessels causing the blood vessels to relaxthereby increasing the supply of blood and oxygen to the heart. Examplesof calcium channel blockers include amlodipine (Norvasc, Lotrel),bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil),nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine(Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

Heart Failure Agents

Agents used to treat heart failure include diuretics, ACE inhibitors,vasodilators, and cardiac glycosides. Diuretics eliminate excess fluidsin the tissues and circulation thereby relieving many of the symptoms ofheart failure. Examples of diuretics include hydrochlorothiazide,metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex),spironolactone (Aldactone), and eplerenone (Inspra).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload onthe heart by expanding the blood vessels and decreasing resistance toblood flow. Examples of ACE inhibitors include benazepril (Lotensin),captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril),lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril(Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril(Mavik).

Vasodilators reduce pressure on the blood vessels by making them relaxand expand. Examples of vasodilators include hydralazine, diazoxide,prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassiumchannel activators, and calcium channel blockers also act asvasodilators.

Cardiac glycosides are compounds that increase the force of the heart'scontractions. These compounds strengthen the pumping capacity of theheart and improve irregular heartbeat activity. Examples of cardiacglycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There arethree main types of antithrombotics—platelet inhibitors, anticoagulants,and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, therebyreducing clotting in the arteries. Examples of platelet inhibitorsinclude acetylsalicylic acid (aspirin), ticlopidine, clopidogrel(plavix), dipyridamole, cilostazol, persantine sulfinpyrazone,dipyridamole, indomethacin, and glycoprotein IIb/IIIa inhibitors, suchas abciximab, tirofiban, and eptifibatide (Integrelin). Beta blockersand calcium channel blockers also have a platelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent theformation of new clots. Examples of anticoagulants include bivalirudin(Angiomax), warfarin (Coumadin), unfractionated heparin, low molecularweight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examplesof thrombolytic agents include streptokinase, urokinase, andtenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate andrhythm. Examples of antiarrhythmic agents include amiodarone,dronedarone, quinidine, procainamide, lidocaine, and propafenone.Cardiac glycosides and beta blockers are also used as antiarrhythmicagents.

Combinations with amiodarone and dronedarone are of particular interestgiven the recently discovered synergistic effects of the sodium channelblocker ranolazine and amioarone and dronedarone.

Antihypertensive Agents

Antihypertensive agents are used to treat hypertension, a condition inwhich the blood pressure is consistently higher than normal.Hypertension is associated with many aspects of cardiovascular disease,including congestive heart failure, atherosclerosis, and clot forillation. Examples of antihypertensive agents include alpha-1-adrenergicantagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura),prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide),and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, suchas propranolol (Inderal), nadolol (Corgard), timolol (Blocadren),metoprolol (Lopressor), and pindolol (Visken); centralalpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres),clonidine hydrochloride and chlorthalidone (Clorpres, Combipres),guanabenz Acetate (Wytensin), guanfacine hydrochloride (Tenex),methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor),methyldopa and hydrochlorothiazide (Aldoril); combinedalpha/beta-adrenergic antagonists, such as labetalol (Normodyne,Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, suchas guanethidine (ismelin), reserpine (Serpasil); central nervoussystem-acting antihypertensives, such as clonidine (Catapres),methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents;ACE inhibitors, such as perindopril (Aceon) captopril (Capoten),enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin-IIreceptor antagonists, such as Candesartan (Atacand), Eprosartan(Teveten), Irbesartan (Avapro), Losartan (Cozaar), Telmisartan(Micardis), Valsartan (Diovan); calcium channel blockers, such asverapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat,Procardia); diuretics; direct vasodilators, such as nitroprusside(Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil(Loniten), verapamil; and potassium channel activators, such asaprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol orfatty sugars present in the blood. Examples of lipid lowering agentsinclude bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, suchas atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor,Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin(Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

In this invention, the patient presenting with an acute coronary diseaseevent often suffers from secondary medical conditions such as one ormore of a metabolic disorder, a pulmonary disorder, a peripheralvascular disorder, or a gastrointestinal disorder. Such patients canbenefit from treatment of a combination therapy comprising administeringto the patient ranolazine in combination with at least one therapeuticagent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to thelungs. Examples of pulmonary disorders include, without limitation,asthma, chronic obstructive pulmonary disease (COPD), bronchitis, andemphysema.

Examples of therapeutics agents used to treat pulmonary disordersinclude bronchodilators including beta2 agonists and anticholinergics,corticosteroids, and electrolyte supplements. Specific examples oftherapeutic agents used to treat pulmonary disorders includeepinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil),salmeterol (Serevent, Serevent Diskus), theophylline, ipratropiumbromide (Atrovent), tiotropium (Spiriva), methylprednisolone(Solu-Medrol, Medrol), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders includeantihypertensive agents and lipid lowering agents, as described in thesection “Cardiovascular Agent Combination Therapy” above. Additionaltherapeutic agents used to treat metabolic disorders include insulin,sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretinmimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels(arteries and veins) located outside the heart and brain, including, forexample peripheral arterial disease (PAD), a condition that developswhen the arteries that supply blood to the internal organs, arms, andlegs become completely or partially blocked as a result ofatherosclerosis.

Gastrointestinal Disorders Combination Therapy

Gastrointestinal disorders refer to diseases and conditions associatedwith the gastrointestinal tract. Examples of gastrointestinal disordersinclude gastroesophageal reflux disease (GERD), inflammatory boweldisease (IBD), gastroenteritis, gastritis and peptic ulcer disease, andpancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disordersinclude proton pump inhibitors, such as pantoprazole (Protonix),lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec),rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine(Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, suchas misoprostoL (Cytotec); sucralfate; and antacids.

Antibiotics, Analgesics, Antidepressants and Anti-Anxiety AgentsCombination Therapy

Patients presenting with an acute coronary disease event may exhibitconditions that benefit from administration of therapeutic agent oragents that are antibiotics, analgesics, antidepressant and anti-anxietyagents in combination with ranolazine.

Antibiotics

Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibioticagents include .beta.-Lactam antibiotics, including penicillins(amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil(Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor),cefuroxime axtel (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid),cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax),cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, andmonobactams; tetracyclines, such as tetracycline; macrolide antibiotics,such as erythromycin; aminoglycosides, such as gentamicin, tobramycin,amikacin; quinolones such as ciprofloxacin; cyclic peptides, such asvancomycin, streptogramins, polymyxins; lincosamides, such asclindamycin; oxazolidinoes, such as linezolid; and sulfa antibiotics,such as sulfisoxazole.

Analgesics

Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphinomimetics, such asfentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Giventhe ability of the sodium channel blockers of the invention to treatneuropathic pain via inhibition of the Nav 1.7 and 1.8 sodium channels,combination with analgesics are particularly envisioned. See U.S. PatentApplication Publication 20090203707.

Antidepressant and Anti-Anxiety Agents

Antidepressant and anti-anxiety agents include those agents used totreat anxiety disorders, depression, and those used as sedatives andtranquillizers. Examples of antidepressant and anti-anxiety agentsinclude benzodiazepines, such as diazepam, lorazepam, and midazolam;benzodiazepines; barbiturates; glutethimide; chloral hydrate;meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem,Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine(Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); venlafaxine(Effexor XR, Efexor); citalopram (Celexa, Cipramil, Talohexane);paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline(Elavil); and bupropion (Wellbutrin, Zyban). Antidepressant andanti-anxiety agents may include neuroactive steroid and ketamine andrelated NMDA receptor antagonists.

Accordingly, one aspect of the invention provides for a compositioncomprising the sodium channel blockers of the invention and at least onetherapeutic agent. In an alternative embodiment, the compositioncomprises the sodium channel blockers of the invention and at least twotherapeutic agents. In further alternative embodiments, the compositioncomprises the sodium channel blockers of the invention and at leastthree therapeutic agents, the sodium channel blockers of the inventionand at least four therapeutic agents, or the sodium channel blockers ofthe invention and at least five therapeutic agents.

The methods of combination therapy include co-administration of a singleformulation containing the sodium channel blockers of the invention andtherapeutic agent or agents, essentially contemporaneous administrationof more than one formulation comprising the sodium channel blocker ofthe invention and therapeutic agent or agents, and consecutiveadministration of a sodium channel blocker of the invention andtherapeutic agent or agents, in any order, wherein preferably there is atime period where the sodium channel blocker of the invention andtherapeutic agent or agents simultaneously exert their therapeuticeffect.

EXEMPLIFICATION

The representative examples that follow are intended to help illustratethe invention, and are not intended to, nor should they be construed to,limit the scope of the invention.

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimal reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include recrystallization,filtration, flash chromatography, trituration, high pressure liquidchromatography (HPLC), or supercritical fluid chromatography (SFC). Notethat flash chromatography may either be performed manually or via anautomated system. The compounds provided herein may be characterized byknown standard procedures, such as nuclear magnetic resonancespectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS).NMR chemical shifts are reported in part per million (ppm) and aregenerated using methods well known to those of skill in the art.

Exemplary general methods for analytical LCMS include Method A (XtimateC18 (2.1 mm×30 mm, 3 μm); A=H₂O (0.04% TFA) and B=CH₃CN (0.02% TFA); 50°C.; 1.2 mL/min; 10-80% B over 0.9 minutes, then 80% B for 0.6 minutes)and Method B (Chromolith Flash RP-18 endcapped C18 (2 mm×25 mm); A=H₂O(0.04% TFA) and B=CH₃CN (0.02% TFA); 50° C.; 1.5 mL/min; 5-95% B over0.7 minutes, then 95% B for 0.4 minutes).

List of Abbreviations

Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride

Pd(t-Bu₃P)₂ bis(tri-tert-butylphosphine)palladium(0)

Pd(OAc)₂ palladium(II) acetate

SPhos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

Et₃N triethylamine

AgOTf silver trifluoromethanesulfonate

DMF N,N-dimethylformamide

MeOH methanol

EtOH ethanol

i-Pr₂O diisopropyl ether

THF tetrahydrofuran

DCM dichloromethane

AcN or MeCN acetonitrile

EA or EtOAc ethyl acetate

PE petroleum ether

DMSO dimethyl sulfoxide

AcOH acetic acid

NB S N-bromosuccinimide

NaOMe sodium methoxide

EtONa sodium ethoxide

TsOH p-toluenesulfonic acid

DEA N,N-diethylaniline

DIPEA N,N-diisopropylethylamine

TFA trifluoroacetic acid

KOAc potassium acetate

T3P propanephosphonic acid anhydride

Example 1:3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridy]-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of B: To a suspension of NaH (2.94 g, 73.56 mmol) in THF (50mL) was added 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) slowly at 20°C., and the mixture was stirred for 1 hour.5-chloro-2,3-difluoro-pyridine (10 g, 66.88 mmol) was then added, andthe mixture was stirred at 20° C. for another 4 hours. The mixture wasquenched with sat.NH₄Cl (50 mL) and extracted with EtOAc (100 mL×2). Thecombined organic phase was washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated to afford B (15000 mg, 65.34 mmol) as an oil.¹H NMR (400 MHz, CDCl₃) δ_(H)=7.83 (d, 1H), 7.38 (dd, 1H), 4.73 (q, 2H).

Synthesis of A3: A mixture of B (8 g, 34.85 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(26.55 g, 104.55 mmol), K₃PO₄ (14.79 g, 69.7 mmol), SPhos (4.29 g, 10.45mmol) and Pd(OAc)₂ (782.4 mg, 3.48 mmol) in 1,4-dioxane (250 mL) wasstirred at 85° C. for 16 hours. After cooling to room temperature, themixture was filtered through Celite and eluted with EtOAc (50 mL×2). Thefiltrate was concentrated and diluted with EtOAc (200 mL), washed withwater (100 mL×2) and brine (100 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified by flashchromatography on silica gel (EtOAc in PE=0 to 10% to 40%) to afford theproduct (3 g, 4.6021 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.26(d, 1H), 7.72 (dd, 1H), 4.87 (q, 2H), 1.35 (s, 12H). LCMS R_(t)=0.94 minusing Method B, MS ESI calcd. for C₁₃H₁₇BF₄NO₃ [M+H]⁺ 322.1, found322.3.

Synthesis of A2: To a mixture of cyclopropylmethanol (382.93 mg, 5.31mmol) in THF (10 mL) was added NaH (212.41 mg, 5.31 mmol), and themixture was stirred at 20° C. for 0.5 hour. Then to the mixture wasadded 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine(300 mg, 1.06 mmol), and the mixture was stirred at 20° C. for 2 hours.The reaction was quenched with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (10 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 40%) to give theproduct (240 mg, 0.73 mmol) as a solid. LCMS Rt=2.29 min in 4 minchromatography.

Synthesis of Compound 1: A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(111.02 mg, 0.35 mmol), Pd(dppf)Cl₂ (34.5 mg, 0.05 mmol),6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine(100 mg, 0.31 mmol) and K₂CO₃ (86.89 mg, 0.63 mmol) in 1,4-Dioxane (5mL) and Water (1 mL) was stirred at 90° C. for 16 hours under N₂. Aftercooling to room temperature, the mixture was filtered through Celite,and eluted with EtOAc (10 mL×2), and the filtrate was concentrated togive the crude product. The crude product was purified by Prep-HPLC(Waters Xbridge 150 mm×25 mm 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN;50-70% B over 7 minutes) to give the product (100.49 mg, 0.23 mmol) as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=8.75 (s, 1H), 8.46 (d, 1H), 8.34(dd, 11.2 Hz, 1H), 8.14-8.09 (m, 1H), 7.97 (dd, 1H), 5.18 (q, 2H), 4.09(d, 2H), 1.31-1.21 (m, 1H), 0.61-0.55 (m, 2H), 0.43-0.37 (m, 2H). LCMSR_(t)=1.31 min in 2.0 min chromatography, MS ESI calcd. for C₁₈H₁₅F₆N₄O₂[M+H]⁺ 433.1, found 433.0.

Example 2:3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A4: To a mixture of 2-methylpropan-1-ol (393.6 mg, 5.31mmol) in THF (10 mL) was added NaH (212.41 mg, 5.31 mmol), and themixture was stirred at 20° C. for 0.5 hour. Then to the mixture wasadded 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine(300 mg, 1.06 mmol), and the mixture was stirred at 20° C. for 2 hours.The reaction was quenched with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (20 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 40%) to give theproduct (100 mg, 0.30 mmol) as a solid. LCMS Rt=0.86 min in 1.5 minchromatography, MS ESI calcd. C₁₁H₁₃BrF₂N₃O [M+H+2]⁺ 320.0, found 320.2.

Synthesis of Compound 2: A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(110.33 mg, 0.34 mmol), Pd(dppf)Cl₂ (34.28 mg, 0.05 mmol),6-bromo-3-[difluoro(isobutoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine(100 mg, 0.31 mmol) and K₂CO₃ (86.35 mg, 0.62 mmol) in 1,4-Dioxane (5mL) and Water (1 mL) was stirred at 90° C. for 16 hours under N₂. Aftercooling to room temperature, the mixture was filtered through Celite,and eluted with EtOAc (10 mL×2), and the filtrate was concentrated togive the crude product. The crude product was purified by Prep-HPLC(Waters Xbridge 150 mm×25 mm 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN;50-70% B over 8 minutes) to give the product (53.41 mg, 0.12 mmol) as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=8.70 (s, 1H), 8.44 (d, 1H), 8.33(dd, 1H), 8.12 (dd, 1H), 7.96 (dd, 1H), 5.18 (q, 2H), 4.02 (d, 2H),2.09-1.98 (m, 1H), 0.96 (d, 6H). LCMS R_(t)=1.34 min in 2.0 minchromatography, MS ESI calcd. for C₁₈H₁₇F₆N₄O₂ [M+H]⁺ 435.1, found435.1.

Example 3:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A5: A mixture of6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300mg, 1.06 mmol) and EtONa (361.37 mg, 5.31 mmol) in Ethanol (10 mL) wasstirred at 80° C. for 24 hours. After cooling to room temperature, thereaction was quenched with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (20 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 40%) to give theproduct (70 mg, 0.17 mmol) as a solid. LCMS R_(t)=1.97 min in 4 minchromatography, MS ESI calcd. C₉H₉BrF₂N₃O [M+H+2]⁺ 294.0, found 293.8.

Synthesis of Compound 3: A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(84.65 mg, 0.26 mmol), Pd(dppf)Cl₂ (26.3 mg, 0.04 mmol),6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70mg, 0.24 mmol) and K₂CO₃ (66.25 mg, 0.48 mmol) in 1,4-Dioxane (5 mL) andWater (1 mL) was stirred at 90° C. for 16 hours under N₂. After coolingto room temperature, the mixture was filtered through Celite, and elutedwith EtOAc (10 mL×2), and the filtrate was concentrated to give thecrude product. The crude product was purified by Prep-HPLC (WatersXbridge 150 mm×25 mm 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 42-62% Bover 8 minutes) to give the product (44.33 mg, 0.11 mmol) as a solid. ¹HNMR (400 MHz, DMSO-d₆) δ_(H)=8.73 (s, 1H), 8.46 (d, 1H), 8.35 (br d,1H), 8.11 (d, 1H), 7.96 (d, 1H), 5.18 (q, 2H), 4.29 (q, 2H), 1.36 (t,3H) LCMS R_(t)=1.25 min in 2.0 min chromatography, MS ESI calcd. forC₁₆H₁₃F₆N₄O₂ [M+H]⁺ 407.1, found 407.0.

Example 4:3-[difluoro(isopropoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A6: To a mixture of propan-2-ol (319.15 mg, 5.31 mmol) inTHF (10 mL) was added NaH (127.45 mg, 3.19 mmol), and the mixture wasstirred at 20° C. for 0.5 hour. Then to the mixture was added6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300mg, 1.06 mmol), and the mixture was stirred at 20° C. for 2 hours. Thereaction was quenched with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (10 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 40%) to give theproduct (240 mg, 0.72 mmol) as a solid. LCMS Rt=2.18 min in 4 minchromatography, MS ESI calcd. C₁₀H₁₁BrF₂N₃O [M+H+2]⁺ 306.0, found 305.9.

Synthesis of Compound 4: A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(115.38 mg, 0.36 mmol), Pd(dppf)Cl₂ (35.85 mg, 0.05 mmol),6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine(100 mg, 0.33 mmol) and K₂CO₃ (90.3 mg, 0.65 mmol) in 1,4-Dioxane (5 mL)and Water (1 mL) was stirred at 90° C. for 16 hours under N₂. Aftercooling to room temperature, the mixture was filtered through Celite,and eluted with EtOAc (10 mL×2), and the filtrate was concentrated togive the crude product. The crude product was purified by Prep-HPLC(Waters Xbridge 150 mm×25 mm 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN;45-65% B over 8 minutes) to give the product (80.25 mg, 0.19 mmol) as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=8.60 (s, 1H), 8.43 (d, 1H), 8.32(dd, 1H), 8.11 (d, 1H), 7.95 (dd, 1H), 5.17 (q, 2H), 4.90 (spt, 1H),1.41 (d, 6H). LCMS R_(t)=1.29 min in 2.0 min chromatography, MS ESIcalcd. for C₁₇H₁₅F₆N₄O₂ [M+H]⁺ 421.1, found 421.0.

Example 5:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A7: To a mixture of (6-chloropyridazin-3-yl)hydrazine (3 g,20.75 mmol) in Toluene (40 mL) was added (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (5.55 g, 22.83 mmol). The reaction mixturewas stirred at 110° C. for 4 hours. After cooling to room temperature,the reaction mixture was concentrated. The residue was diluted withsaturated NaHCO₃ (50 mL), and the mixture was extracted with EtOAc (50mL×2). The combined organic phase was washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=8.67 (d, 1H), 7.78 (d, 1H).

Synthesis of A9: A mixture of6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine(200 mg, 0.84 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(350.58 mg, 1 mmol), Pd(t-Bu₃P)₂ (64.15 mg, 0.13 mmol), and K₃PO₄(532.95 mg, 2.51 mmol) in 1,4-Dioxane (2 mL) and Water (0.20 mL) wasstirred at 80° C. for 16 hours. After cooling to room temperature, thesuspension was diluted with EtOAc (10 mL), filtered through silica gel,eluted with EtOAc (20 mL). The combined filtrates were concentrated toafford crude product. The crude product was purified by flashchromatograph on silica gel (EtOAc in PE=20% to 50% to 80%) to give theproduct (260 mg, 0.50 mmol) as a solid. LCMS R_(t)=0.96 min in 1.5 minchromatography, MS ESI calcd. for C₁₅E₁₁ClF₆N₅O [M+H]⁺ 426.1, found425.9.

Synthesis of Compound 5: To a mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridy]-[1,2,4]triazolo[4,3-b]pyridazine(150 mg, 0.35 mmol) in MeCN (1 mL) was added AgOTf (905.31 mg, 3.52mmol) and MeOH (8 mL, 0.35 mmol). The mixture was stirred at 90° C. for10 days. After cooling to room temperature, the mixture was concentratedto give a residue. The residue was diluted with water (30 mL), extractedwith EtOAc (30 mL×2). The combined organic phase was washed with water(20 mL×2), brine (30 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby Prep-HPLC (Waters Xbridge 150 mm×25 mm, 5 μm), A=H₂O (0.05% NH₄OH)and B=CH₃CN; 57-87% B over 9 minutes) to give the product as a solid. ¹HNMR (CDCl₃, 400 MHz) δ_(H)=8.55 (d, 1H), 8.29 (d, 1H), 8.09 (dd, 1H),7.65 (d, 1H), 3.94 (s, 3H), 1.90 (s, 6H). LCMS R_(t)=1.32 min in 2.0 minchromatography, MS ESI calcd. for C₁₆H₁₄F₆N₅O₂ [M+H]⁺ 422.1, found422.0.

Example 6:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100mg, 360 μmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(144.62 mg, 430 μmol), K₂CO₃ (99.41 mg, 720 μmol) and Pd(dppf)Cl₂ (39.47mg, 50 μmol) in 1,4-Dioxane (5 mL) and Water (500 μL) was stirred at 80°C. for 12 hours under N₂. After cooling to room temperature, the mixturewas diluted with H₂O (10 mL), and the mixture was extracted with EtOAc(20 mL×2). The combined organic phase was washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-HPLC (Boston PrimeC18 (150×30 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN; 53-83% B over 8minutes) to give the product as a solid. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=8.73 (s, 1H), 8.45 (d, 1H), 8.33 (dd, 1H), 8.10 (d, 1H), 7.94 (d,1H), 6.01 (spt, 1H), 3.89 (s, 3H), 1.54 (d, 3H). LCMS R_(t)=1.27 min in2.0 min chromatography, MS ESI calcd. C₁₈H₁₃F₆N₄O₂ [M+H]⁺ 407.09, found406.9.

Example 7:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100mg, 360 μmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(144.62 mg, 430 μmol), K₂CO₃ (99.41 mg, 720 μmol) and Pd(dppf)Cl₂ (39.47mg, 50 μmol) in 1,4-Dioxane (5 mL) and Water (500 μL) was stirred at 80°C. for 12 hours under N₂. After cooling to room temperature, the mixturewas diluted with H₂O (10 mL), and the mixture was extracted with EtOAc(20 mL×2). The combined organic phase was washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-HPLC (Boston PrimeC18 (150 mm×30 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN; 53-83% B over8 minutes) to give the product as a solid. ¹H-NMR (400 MHz, DMSO-d₆)δ_(H)=8.74 (s, 1H), 8.46 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H), 7.95 (dd,1H), 6.02 (spt, 1H), 3.95-3.82 (m, 3H), 1.55 (d, 3H). LCMS R_(t)=1.27min in 2.0 min chromatography, MS ESI calcd. C₁₈H₁₃F₆N₄O₂ [M+H]⁺ 407.1,found 406.9.

Example 8:3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(300 mg, 0.75 mmol) and AgOTf (1938.39 mg, 7.54 mmol) incyclopropylmethanol (15 mL, 0.75 mmol) and CH₃CN (15 mL) was stirred at90° C. for 14 days. After cooling to room temperature, the reaction wasdiluted with EtOAc (40 mL), and to the mixture was added saturated NaCl(40 mL), the mixture was filtered through Celite and eluted with EtOAc(20 mL×2), and the filtrate was concentrated to give the crude product.The crude product was purified by Prep-TLC (EtOAc:PE=1:1) to give theimpure product. The impure product was purified by Prep-HPLC (WatersXbridge 150 mm×25 mm 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 48-68% Bover 8 minutes) to give the product as a solid. ¹H-NMR (CDCl₃, 400 MHz)δ_(H)=9.52 (d, 1H), 8.57 (d, 1H), 8.50 (d, 1H), 8.07 (dd, 1H), 4.93 (q,2H), 4.13 (d, 2H), 1.40-1.30 (m, 1H), 0.79-0.73 (m, 2H), 0.49-0.42 (m,2H). LCMS R_(t)=1.33 min in 2.0 min chromatography, MS ESI calcd. forC₁₇H₁₄F₆N₅O₂ [M+H]⁺ 434.1, found 434.0.

Example 9:3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A19: A mixture of Pd(dppf)Cl₂ (15.13 g, 20.68 mmol), Cs₂CO₃(269.49 g, 827.17 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(141.18 g, 439.69 mmol) and 2-bromo-5-chloro-pyrazine (80 g, 413.59mmol) in 1,4-Dioxane (1 L) and Water (150 mL) under N₂ was stirred at35° C. for 2 hours. After cooling to room temperature, to the mixturewas added water (300 mL) and the mixture was filtered through Celite.After separating, the organic phase was washed with brine (300 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was re-dissolved in EA/PE=1/3 (500 mL) andthen filtered through silica gel mat. The cake was washed with EA/PE=1/3(500 mL). The combined organic phase was concentrated to give a residueas oil. To the oil was added PE (500 mL) slowly and some solid wasobtained. The solid was collected and dried in oven to give the product(100 g, 242.4 mmol, 58% yield) as a solid. LCMS R_(t)=1.28 min in 2.0min chromatography, 10-80AB, MS ESI calcd. for C₁₁H₇ClF₄N_(3l O [M+H]) ⁺308.0, found 307.9.

Synthesis of A20: A mixture of2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (140g, 339.36 mmol) and hydrazine; hydrate (169.88 g, 3393.6 mmol) in MeCN(1.4 L) was stirred at 100° C. for 16 hours. After cooling to roomtemperature, the mixture was poured into water (4.5 L). Some solid wasobserved and the solid was collected by filtered. The cake was washedwith water (500 mL×2). The solid was re-dissolved in EtOAc (3 L), washedwith brine (500 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product (100 g, 329.8 mmol, 97% yield) asa solid. LCMS R_(t)=0.74 min in 1.5 min chromatography, 5-95AB, MS ESIcalcd. for C₁₁H₁₀F₄N₅O [M+H]⁺ 304.1, found 303.9.

Synthesis of A13: To a solution of 2-bromo-2,2-difluoro-acetic acid (87g, 497.34 mmol) in THF (1 L) was added one drop of DMF and (COCl)₂ (50.5mL, 596.81 mmol). The resulting mixture was stirred at 20° C. for 1hour. The resulting solution was used into next step directly. To thesolution of 2-bromo-2,2-difluoro-acetyl chloride (95.66 g, 494.69 mmol)in THF (1 L) was added[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine(100 g, 329.79 mmol). The resulting mixture was stirred at 20° C. for 2hours. To the solution was added water (1 L), extracted with EtOAc(1L×2). The combined organic phase was washed with brine (500 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct (150 g, 326.0 mmol, 98% yield, mixture of mono- andbis-alkylated products) as a solid. LCMS R_(t)=0.92 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for C₁₃H₉BrF₆N₅O₂ [M+H]⁺ 460.1,found 459.8.

Synthesis of A14: A solution of2-bromo-2,2-difluoro-N′-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]acetohydrazide(150 g, 325.99 mmol) and TsOH (16.84 g, 97.8 mmol) in Toluene (1.5 L)was stirred at 130° C. for 16 hours. After cooling to room temperature,the mixture was poured into water (2 L), extracted with EtOAc (2L×2).The combined organic phase was washed with brine (1 L×2), dried overanhydrous Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by chromatography flash on siliga gel(EtOAc in PE=0% to 15% to 30%) to give the product (80 g, 181.0 mmol,55% yield) as oil. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=9.60 (d, 1H), 8.55 (d,1H), 8.45 (s, 1H), 8.09 (dd, 1H), 4.93 (q, 2H).

Synthesis of Compound 10: A mixture of3-[bromo(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(76 g, 171.9 mmol) and AgBF₄ (66.93 g, 343.81 mmol) in Ethanol (760 mL)was stirred at 60° C. for 1 hour. After cooling to room temperature, themixture was poured into saturated aqueous NaCl (1 L) and EtOAc (2 L).The mixture was filtered through Celite. After separating, the aqueouslayer was extracted with EtOAc (500 mL×2). The combined organic phasewas washed with brine (500 mL×2), dried over anhydrous Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by chromatography flash column on silica gel (EtOAc in PE=0% to30% to 50%) and then triturated from EtOH (50 mL) to give the product(44.45 g, 109.01 mmol, 63% yield) as a solid. ¹H NMR (CDCl₃ 400 MHz)δ_(H)=9.52 (d, 1H), 8.49 (dd, 2H), 8.07 (dd, 1H), 4.93 (q, 2H), 4.37 (q,2H), 1.51 (t, 3H). LCMS R_(t)=1.25 min in 2.0 min chromatography,10-80AB, MS ESI calcd. for C₁₅H₁₂F₆N₅O₂ [M+H]⁺ 408.1, found 408.0.

Example 10:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(1.4 g, 3.2 mmol) and AgOTf (8.22 g, 31.98 mmol), in mixed solventMethanol (14 mL) and DMF (14 mL) was stirred at 90° C. for 24 hours.After cooling to room temperature, the reaction mixture was treated withbrine (40 mL), and the precipitate was filtered. The filtrate wasextracted with EtOAc (40 mL×2). The combined organic phase was washedwith brine (20 mL), dried over Na₂SO₄ and concentrated to give a crudeproduct. The crude product was purified by Prep-HPLC (Waters Xbridge(150 mm×25 mm 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 57-67% B over 8minutes) to give the product (240 mg). Another batch was started with1.2 g of A24, and about 110 mg of the product was obtained by Prep-HPLC(Boston Prime C18 (150 mm×30 mm, 5 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN;50-80% B over 9 minutes). Two batches of the product were combined andlyophilized to give the product as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=9.51 (d, 1H), 8.49 (d, 1H), 8.47 (d, 1H), 8.05 (dd, 1H), 3.98 (s,3H), 2.98-2.86 (m, 2H), 2.81-2.72 (m, 2H), 2.11-1.93 (m, 2H). LCMSR_(t)=1.30 min in 2 min chromatography, 10-80AB, MS ESI calcd. forC₁₇H₁₄F₆N₅O₂ [M+H]⁺ 434.1, found 433.9.

Example 11:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A25: A mixture of6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine(120 mg, 0.50 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(201.9 mg, 0.60 mmol), K₃PO₄ (319.74 mg, 1.51 mmol), Pd(t-Bu₃P)₂ (25.66mg, 0.05 mmol) in 1,4-dioxane (12 mL) and H₂O (4 mL) was stirred at 90°C. for 16 hours. After cooling to room temperature, the reaction mixturewas concentrated, diluted with water (20 mL), and extracted with ethylacetate (20 mL×2). The combined organic phase was washed with brine (40mL), dried over Na₂SO₄ and concentrated to give a residue. The residuewas purified by flash chromatography on silica gel (EtOAc in PE=0% to60%) to give the product (120 mg, 0.29 mmol) as a solid. ¹11-NMR (CDCl₃,400 MHz) δ_(H)=8.57 (d, 1H), 8.35 (d, 1H), 8.15 (dd, 1H), 7.74 (d, 1H),5.93 (m, 1H) 1.61 (d, 3H).

Synthesis of Compound 12: A mixture of AgOTf (599.15 mg, 2.33 mmol),3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine(120 mg, 0.29 mmol) in methanol (6 mL) was stirred at 90° C. for 120hours. After cooling to room temperature, the reaction mixture wastreated with brine (20 mL), and the precipitate was filtrated. Thefiltrate was concentrated, diluted with water (20 mL), and extractedwith ethyl acetate (20 mL×2). The combined organic phase was washed withbrine (40 mL), dried over Na₂SO₄ and concentrated to give a residue. Theresidue was purified by prep-HPLC (Boston Prime C18 150×30 mm 5 μm)A=H₂O (0.05% NH₄OH) and B=CH₃CN; 52-82% B over 8 minutes) to give theproduct (5.12 mg, 13 μmol). ¹H-NMR (CDCl₃, 400 MHz) δ_(H)=8.55 (d, 1H),8.30 (d, 1H), 8.14 (dd, 1H), 7.66 (d, 1H), 5.92 (m, 1H), 3.94 (s, 3H),1.61 (d, 3H). LCMS R_(t)=1.28 min in 2.0 min chromatography, MS ESIcalcd. for C₁₅H₁₂F₆N₅O₂ [M+H]⁺ 408.1, found 408.0.

Example 12:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A26: A mixture of6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine(120 mg, 0.50 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(201.9 mg, 0.60 mmol), K₃PO₄ (319.74 mg, 1.51 mmol), Pd(t-Bu₃P)₂ (25.66mg, 0.05 mmol) in 1,4-dioxane (12 mL) and H₂O (4 mL) at 90° C. for 16hours. After cooling to room temperature, the reaction mixture wasconcentrated to remove solvent, diluted with water (20 mL) and extractedwith ethyl acetate (20 mL×2). The combined organic phase was washed withbrine (40 mL), dried over Na₂SO₄ and concentrated to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 60%) to give the product (140 mg, 0.34mmol) as a solid. ¹11-NMR (CDCl₃, 400 MHz) δ_(H)=8.57 (d, 1H), 8.35 (d,1H), 8.14 (dd, 1H), 7.74 (d, 1H), 5.93 (m, 1H), 1.61 (d, 3H).

Synthesis of Compound 13: A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine(140 mg, 0.34 mmol), AgOTf (699 mg, 2.72 mmol) in methanol (8 mL) andwas stirred at 90° C. for 120 hours. After cooling to room temperature,the reaction mixture was treated with brine (20 mL), and the precipitatewas filtrated. The filtrate was concentrated and diluted with water (20mL), then extracted with ethyl acetate (20 mL×2). The combined organicphase was washed with brine (40 mL), dried over Na₂SO₄ and concentratedto give a residue. The residue was purified by Prep-HPLC (Boston PrimeC18 150×30 mm 5 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN; 52-82% B over 8minutes) to give the product (5 mg, 12.2 μmol). ¹H-NMR (CDCl₃, 400 MHz)δ_(H)=8.55 (d, 1H), 8.30 (d, 1H), 8.14 (dd, 1H), 7.66 (d, 1H), 5.92 (m,1H), 3.94 (s, 3H), 1.61 (d, 3H). LCMS R_(t)=1.26 min in 2.0 minchromatography MS ESI calcd. for C₁₅H₁₂F₆N₅O₂ [M+H]⁺ 408.1, found 408.0.

Example 13:3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A27: A mixture of6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine(500 mg, 2.09 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(2015.06 mg, 6.28 mmol), Pd(t-Bu₃P)₂ (160.37 mg, 0.31 mmol) and K₃PO₄(888.25 mg, 4.18 mmol) in 1,4-Dioxane (15 mL) and Water (1.5 mL) wasstirred at 90° C. for 16 hours under N₂. The mixture was filteredthrough Celite, and eluted with EtOAc (10 mL×2), and the filtrate wasconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=20% to 60%) to givethe product (900 mg, 1.90 mmol) as a solid. LCMS Rt=0.85 min in 1.5 minchromatography, MS ESI calcd. C₁₃H₇ClF₆N₅O [M+H]⁺ 398.0, found 398.0.

Synthesis of Compound 14: A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine(200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) incyclopropylmethanol (10 mL, 0.50 mmol) and CH₃CN (10 mL) was stirred at90° C. for 13 days. After cooling to room temperature, the reaction wasdiluted with EtOAc (40 mL) and brine (40 mL). The mixture was filteredthrough Celite, eluted with EtOAc (20 mL×2), and the filtrate wasconcentrated to give the crude product. The crude product was purifiedby Prep-HPLC (Boston Prime C18 150 mm×30 mm 5 μm) A=H₂O (0.05% NH₄OHv/v) and B=CH₃CN; 58-88% B over 8 minutes) to give the impure product.The impure product was triturated from n-hexane/i-Pr₂O (v/v=1:1, 2 mL)to give the product (9.82 mg, 22.2 μmol) as a solid. ¹H NMR (DMSO-d₆,400 MHz) δ_(H)=8.83 (d, 1H), 8.67 (d, 1H), 8.45 (dd, 1H), 8.21 (d, 1H),5.22 (q, 2H), 4.03 (d, 2H), 1.26-1.18 (m, 1H), 0.62-0.54 (m, 2H),0.43-0.33 (m, 2H). LCMS R_(t)=2.87 min in 4.0 min chromatography, MS ESIcalcd. for C₁₇H₁₄F₆N₅O₂ [M+H]⁺ 434.1, found 434.0.

Example 14:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A29: A solution of[5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine(300 mg, 0.91 mmol) and (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (660.02 mg, 2.72 mmol) in Toluene (30 mL)was stirred at 110° C. for 72 hours. After cooling to room temperature,the mixture was concentrated to give a residue. To the residue was addedwater (50 mL), and the mixture was extracted with EtOAc (50 mL×2). Thecombined organic phase was washed with water (50 mL), brine (50 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by flash chromatography columnon silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (150mg, 346.3 μmol) as a solid. LCMS R_(t)=3.06 min in 4.0 minchromatography, MS ESI calcd. for C₁₅H₁₁ClF₆N₅O [M+H]⁺ 426.0, found426.0.

Synthesis of Compound 15: To a solution of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(150 mg, 0.35 mmol) in Methanol (5 mL) and MeCN (5 mL) was added AgOTf(1.81 g, 7.05 mmol). The resulting mixture was stirred at 90° C. in asealed tube under N₂ for 5 days. The mixture was cooled to roomtemperature and then brine (20 mL) and EtOAc (30 mL) were added and themixture was filtered. After the filtrate was separated, the organicphase was washed with water (20 mL×2), brine (20 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by Prep-TLC (PE:EtOAc=4:1) to give theproduct (14.23 mg, 33.2 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=9.52 (d, 1H), 8.51 (d, 1H), 8.45 (d, 1H), 8.02 (dd, 1H), 3.98 (s,3H), 1.89 (s, 6H). LCMS R_(t)=1.33 min in 2.0 min chromatography, MS ESIcalcd. for C₁₆H₁₄F₆N₅O₂ [M+H]⁺ 422.1, found 422.0.

Example 15:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine(200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) in ethanol (10 mL,0.50 mmol) and CH₃CN (10 mL) was stirred at 90° C. for 13 days. Aftercooling to room temperature, the reaction was diluted with EtOAc (40 mL)and brine (40 mL). The mixture was filtered through Celite, eluted withEtOAc (20 mL×2), and the filtrate was concentrated to give the crudeproduct. The crude product was purified by Prep-TLC (EtOAc:DCM:PE=1:1:1)to give the impure product. The impure product was triturated fromn-hexane/CH₂Cl₂ (v/v=1:2, 6 mL) to give the product (15.95 mg, 39.2mmol) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.81 (d, 1H), 8.68 (d,1H), 8.43 (dd, 1H), 8.21 (d, 1H), 5.22 (q, 2H), 4.24 (q, 2H), 1.36 (t,3H). LCMS R_(t)=1.26 min in 2.0 min chromatography, MS ESI calcd. forC₁₅H₁₂F₆N₅O₂ [M+H]⁺ 408.1, found 408.0.

Example 16:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A7-a: To a mixture of (6-chloropyridazin-3-yl)hydrazine(3.0 g, 20.75 mmol) in toluene (40 mL) was added(2-chloro-2,2-difluoro-acetyl)-2-chloro-2,2-difluoro-acetate (7.56 g,31.13 mmol). The reaction mixture was stirred at 110° C. for 4 hours.After cooling to room temperature, the reaction mixture wasconcentrated. The residue was diluted with sat. NaHCO₃ (50 mL), and themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product (4700 mg, 19.66 mmol) as a solid.¹H NMR (400MHZ, CDCl₃) δ_(H)=7.35 (d, 1H), 8.23 (d, 1H).

Synthesis of A30: A mixture of6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine(150 mg, 0.63 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine(362.64 mg, 1 mmol), K₃PO₄ (399.65 mg, 1.88 mmol),Bis(tri-tert-butylphosphine) palladium(0) (64.15 mg, 0.1300 mmol) in1,4-Dioxane (12 mL) and Water (4 mL) was stirred at 80° C. for 16 hours.From TLC, new spot (Rf=0.45, UV) was observed, and no starting material(Rf=0.8, UV) remained. After cooling to room temperature, the reactionmixture was concentrated to remove solvent, diluted with water (20 mL)and extracted with ethyl acetate (20 mL×2). The combined organic phasewas washed with brine (40 mL), dried over Na₂SO₄ and concentrated togive the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 60%) to give the product(120 mg, 0.27 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.57 (d,1H), 8.33 (d, 1H), 8.15-8.06 (m, 1H), 7.73 (d, 1H), 2.82-2.96 (m, 2H),2.78-2.81 (m, 2H), 2.00-2.08 (m, 2H).

Synthesis of Compound 17: A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine(120 mg, 0.27 mmol), silver trifluoromethanesulfonate (0.7 g, 2.74mmol), in mixed solvent methanol (12 mL) and MeCN (4 mL) was stirred at80° C. for 72 hours. After cooling to room temperature, the reactionmixture was treated with brine (20 mL) and the precipitate wasfiltrated. The filtrate was concentrated to remove solvent, and dilutedwith water (20 mL), and extracted with ethyl acetate (20 mL×2). Thecombined organic phase was washed with brine (40 mL), dried over Na₂SO₄and concentrated to give a residue. The crude product was purified byprep-HPLC (Boston Prime C18 150×30 mm 5 μm) A=H₂O (0.05% NH₄OH) andB=ACN; 52-82% B over 8 minutes) to give the product (27.93 mg, 64.5μmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.54 (d, 1H), 8.28 (d,1H), 8.11 (dd, 1H), 7.64 (d, 1H), 3.93 (s, 3H), 2.82-2.96 (m, 2H),2.76-2.81 (m, 2H), 1.57-2.07 (m, 2H). LCMS R_(t)=1.32 min in 2.0 minchromatography, MS ESI calcd. for C₁₇H₁₄F₆N₅O₂ [M+H]⁺434.1, found 434.0.

Example 17:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A1: A mixture of (5-bromo-2-pyridyl)hydrazine (2.6 g, 13.83mmol) and (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate(5.04 g, 20.74 mmol) in toluene (100 mL) was stirred at 10° C. for 1hour, and then the mixture was warmed to 120° C. and stirred for 36hours. After cooling to room temperature, the reaction was quenched withsaturated NaHCO₃ (50 mL), and the mixture was extracted with EtOAc (50mL×2). The organic layer was washed with brine (50 mL), drived overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 20% to 30%) to give the product (3900 mg, 13.81 mmol) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.42 (s, 1H), 7.84 (d, 1H), 7.53(dd, 1H). LCMS R_(t)=3.19 min in 7.0 min chromatography, MS ESI calcd.for C₇H₄BrClF₂N₃ [M+H+2]⁺283.9, found 283.6.

Synthesis of A15: A mixture of6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1 g,3.54 mmol) and NaOMe (956.21 mg, 17.7 mmol) in Methanol (20 mL) wasstirred at 80° C. for 24 hours. After cooling to room temperature, thereaction was quenched with sat.NH₄Cl (50 mL), and the mixture wasextracted with EtOAc (50 mL×2). The combine organic layer was washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 30% to 40%) to give theproduct (380 mg, 127.56 μmol) as a solid. ¹11-NMR (CDCl₃, 400 MHz)δ_(H)=8.43 (s, 1H), 7.77 (d, 1H), 7.47-7.41 (m, 1H), 3.92 (s, 3H). LCMSR_(t)=2.95 min in 7.0 min chromatography, MS ESI calcd. for C₈H₇BrF₂N₃O[M+H+2]⁺280.0, found 279.7.

Synthesis of Compound 18: A mixture of6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100mg, 0.36 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine(155.86 mg, 0.43 mmol), K₂CO₃ (99.41 mg, 0.72 mmol) and Pd(dppf)Cl₂(39.47 mg, 0.05 mmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL) wasstirred at 80° C. for 12 hours. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (30mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 (150×30 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN;58-88% B over 8 minutes) to give the product (66.89 mg, 15.47 μmol) as asolid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.75 (s, 1H), 8.46 (d, 1H), 8.33(dd, 1H), 8.10 (d, 1H), 7.96 (dd, 1H), 3.89 (s, 3H), 2.97-2.85 (m, 2H),2.72-2.62 (m, 2H), 2.07-1.95 (m, 1H), 1.93-1.81 (m, 1H). LCMS R_(t)=1.32min in 2.0 min chromatography, MS ESI calcd. C₁₈H₁₅F₆N₄O₂ [M+H]⁺ 433.1,found 432.9.

Example 18: Synthesis of3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine(65 mg, 200 μmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(82.16 mg, 250 μmol), K₂CO₃ (56.48 mg, 410 μmol) and Pd(dppf)Cl₂ (22.43mg, 30 μmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at80° C. for 12 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (20mL) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 (150×30 mm, 5 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN;62-92% B over 8 minutes) yielding the product (43.42 mg, 97.3 μmol, 48%yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.74 (s, 1H), 8.44(d, 1H), 8.32 (dd, 1H), 8.11 (dd, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H),4.09 (d, 2H), 1.54 (d, 3H), 1.32-1.21 (m, 1H), 0.62-0.52 (m, 2H),0.44-0.33 (m, 2H). LCMS R_(t)=1.37 min in 2.0 min chromatography,10-80AB, MS ESI calcd. C₁₉H₁₇F₆N₄O₂ [M+H]⁺ 447.1, found 447.0.

Example 19:3-[difluoro(isopropoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine(70 mg, 230 μmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(91.96 mg, 270 μmol), K₂CO₃ (63.21 mg, 460 μmol) and Pd(dppf)Cl₂ (25.1mg, 30 μmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at80° C. for 12 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (20mL) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 (150×30 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN;60-90% B over 8 minutes) to give the product (33.94 mg, 78.1 μmol, 34%yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.61 (s, 1H), 8.43(d, 1H), 8.31 (dd, 1H), 8.11 (dd, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H),4.90 (spt, 1H), 1.54 (d, 3H), 1.41 (d, 6H). LCMS R_(t)=1.35 min in 2.0min chromatography, 10-80AB, MS ESI calcd. C₁₈H₁₇F₆N₄O₂ [M+H]⁺ 435.1,found 435.0.

Example 20:3-[difluoro(isopropoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(84.29 mg, 0.25 mmol), Pd(dppf)Cl₂ (25.1 mg, 0.03 mmol),6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine(70 mg, 0.23 mmol) and K₂CO₃ (63.21 mg, 0.46 mmol) in 1,4-Dioxane (5 mL)and Water (1 mL) was stirred at 90° C. for 16 hours under N₂. Aftercooling to room temperature, the mixture was filtered through Celite,and eluted with EtOAc (10 mL×2), and the filtrate was concentrated togive the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 (150 mm×30 mm 5 μm) A=H₂O (0.05% ammonia hydroxidev/v) and B=CH₃CN; 60-90% B over 8 minutes) to give the product (24.78mg, 57.1 μmol, 25% yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz)δ_(H)=8.61 (s, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.12 (d, 1H), 7.95 (dd,1H), 6.03 (spt, 1H), 4.95-4.85 (m, 1H), 1.54 (d, 3H), 1.41 (d, 6H). LCMSR_(t)=1.37 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. forC₁₈H₁₇F₆N₄O₂ [M+H]⁺ 435.1, found 435.1.

Example 21:3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A1-a: A mixture of (5-bromo-2-pyridyl)hydrazine (5 g, 26.59mmol) and (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate(9690.21 mg, 39.89 mmol) in Toluene (200 mL) was stirred at 10° C. for 1hour, and then the mixture was heated at 120° C. for 36 hours. Aftercooling to room temperature, the reaction was quenched with sat. NaHCO₃(200 mL), then the mixture was extracted with EtOAc (80 mL×2). Theorganic layer was washed with brine (200 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to 5%to 20%) to give the product (5700 mg, 20.18 mmol, 76% yield) as a solid.¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.43 (s, 1H), 7.84 (dd, 1H), 7.54 (dd,1H).

Synthesis of A4-a: To a mixture of 2-methylpropan-1-ol (1312 mg, 17.7mmol) in THF (40 mL) was added NaH (708.04 mg, 17.7 mmol), and themixture was stirred at 20° C. for 0.5 hour. Then to the mixture wasadded 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine(1000 mg, 3.54 mmol), and the mixture was stirred at 20° C. for 2 hours.The reaction was quenched with sat. NH₄Cl (40 mL), and the mixture wasextracted with EtOAc (30 mL×2). The combined organic phase was washedwith brine (70 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 40%) to give theproduct (750 mg, 2.34 mmol, 66% yield) as an oil. ¹H NMR (CDCl₃, 400MHz) δ_(H)=8.44 (s, 1H), 7.77 (d, 1H), 7.44 (dd, 1H), 4.00 (d, 2H),2.16-2.06 (m, 1H), 1.04 (d, 6H).

Synthesis of Compound 22: A mixture of6-bromo-3-[difluoro(isobutoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine(100 mg, 310 μmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(125.61 mg, 370 μmol), K₂CO₃ (86.35 mg, 620 μmol) and Pd(dppf)Cl₂ (34.28mg, 50 μmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at80° C. for 12 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and then extracted with EtOAc (20mL×2). The combined organic phase was washed with water (20 mL) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-HPLC (Boston PrimeC18 (150×30 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN; 65-95% B over 8minutes) to give the product (47.11 mg, 105.1 μmol, 34% yield) as asolid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.70 (s, 1H), 8.43 (d, 1H), 8.31(dd, 1H), 8.11 (dd, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H), 4.01 (d, 2H),2.10-1.95 (m, 1H), 1.54 (d, 3H), 0.96 (d, 6H). LCMS R_(t)=1.41 min in2.0 min chromatography, 10-80AB, MS ESI calcd. C₁₉H₁₉F₆N₄O₂ [M+H]⁺449.1, found 449.1.

Example 22:3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(115.14 mg, 0.34 mmol), Pd(dppf)Cl₂ (34.28 mg, 0.05 mmol),6-bromo-3-[difluoro(isobutoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine(100 mg, 0.31 mmol) and K₂CO₃ (86.35 mg, 0.62 mmol) in 1,4-Dioxane (5mL) and Water (1 mL) was stirred at 90° C. for 16 hours under N₂. Aftercooling to room temperature, the mixture was filtered through Celite,and eluted with EtOAc (10 mL×2), and the filtrate was concentrated togive the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 150 mm×30 mm 5 μm) A=H₂O (0.05% ammonia hydroxide v/v)and B=CH₃CN; 61-91% B over 8 minutes) to give the product (68.11 mg,0.15 mmol, 48% yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.70(s, 1H), 8.43 (d, 1H), 8.31 (dd, 1H), 8.15-8.09 (m, 1H), 7.95 (dd, 1H),6.08-5.96 (m, 1H), 4.02 (d, 2H), 2.09-1.96 (m, 1H), 1.54 (d, 3H), 0.96(d, 6H). LCMS R_(t)=1.42 min in 2.0 min chromatography, 10-80ABMS ESIcalcd. for C₁₉H₁₉F₆N₄O₂ [M+H]⁺ 449.1, found 449.1.

Example 23:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A15-a: A mixture of6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1000mg, 3.54 mmol) and NaOMe (956.21 mg, 17.7 mmol) in Methanol (20 mL) wasstirred at 80° C. for 24 hours. After cooling to room temperature, thereaction was quenched with sat. NH₄Cl (50 mL), then the mixture wasextracted with EtOAc (50 mL×2). The organic layer was washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 30% to 40%) to give the product (230 mg,754.3 μmol, 21% yield) as an oil. LCMS R_(t)=1.41 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. C₈H₈BrF₂N₃O [M+H+2]⁺280.0, found279.9.

Synthesis of Compound 24: A mixture of6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70mg, 250 μmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(105.47 mg, 300 μmol), K₂CO₃ (69.59 mg, 500 μmol) and Pd(dppf)Cl₂ (27.63mg, 40 μmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at80° C. for 12 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (20 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (30mL) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 (150×30 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN;56-86% B over 8 minutes) to give the product (22.72 mg, 54.1 μmol, 21%yield) as a solid. ⁺H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.75 (s, 1H), 8.47(d, 1H), 8.31 (dd, 1H), 8.14-8.05 (m, 1H), 7.95 (dd, 1H), 3.89 (s, 3H),1.82 (s, 6H). LCMS R_(t)=1.31 min in 2.0 min chromatography, 10-80AB, MSESI calcd. C₁₇H₁₅F₆N₄O₂ [M+H]⁺ 421.1, found 421.1.

Example 24:3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(69.52 mg, 0.21 mmol), Pd(dppf)Cl₂ (20.7 mg, 0.03 mmol),6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine(60 mg, 0.19 mmol) and K₂CO₃ (52.14 mg, 0.38 mmol) in 1,4-Dioxane (5 mL)and Water (1 mL) was stirred at 90° C. for 16 hours under N₂. Aftercooling to room temperature, the mixture was filtered through Celite,and eluted with EtOAc (10 mL×2), and the filtrate was concentrated togive the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 150 mm×30 mm 5 μm) A=H₂O (0.05% ammonia hydroxide v/v)and B=CH₃CN; 60-90% B over 8 minutes) to give the product (51.82 mg,0.12 mmol, 62% yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.74(s, 1H), 8.45 (d, 1H), 8.32 (dd, 1H), 8.11 (dd, 1H), 7.96 (dd, 1H), 6.02(spt, 1H), 4.09 (d, 2H), 1.54 (d, 3H), 1.32-1.21 (m, 1H), 0.62-0.54 (m,2H), 0.43-0.36 (m, 2H). LCMS R_(t)=1.39 min in 2.0 min chromatography,10-80ABMS ESI calcd. for C₁₉H₁₇F₆N₄O₂ [M+H]⁺ 447.1, found 447.1.

Example 25:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(500 mg, 1.21 mmol) and AgOTf (3120.55 mg, 12.15 mmol) in Ethanol (7 mL)and MeCN (7 mL) was stirred at 90° C. for 5 days. The mixture was cooledto room temperature then EtOAc (20 mL) and brine (50 mL) were added tothe mixture, the resulting suspension was filtered through Celite. Thefiltrate was separated and the aqueous phase was extracted with EtOAc(50 mL). The combined organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by chromatography flash on silica gel (EtOAc in PE=10% to30% to 50%) and then triturated from DCM (3 mL) and n-hexane (4 mL) togive the product (31.35 mg, 74 μmol, 6% yield) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=9.52 (d, 1H), 8.48 (dd, 2H), 8.04 (dd, 1H),5.95-5.87 (m, 1H), 4.37 (q, 2H), 1.60 (d, 3H), 1.51 (t, 3H). LCMSR_(t)=1.35 min in 2 min chromatography, 10-80AB, MS ESI calcd. forC₁₆H₁₄F₆N₅O₂ [M+H]⁺ 422.1, found 422.1.

Example 26:6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine(100 mg, 0.5 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(210.94 mg, 0.6 mmol), K₃PO₄ (213.79 mg, 1.01 mmol), Pd(t-Bu₃P)₂ (38.6mg, 0.08 mmol) in 1,4-Dioxane (5 mL) and Water (0.5 mL) was stirred at80° C. for 16 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (10mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 (150 mm×30 mm, 5 μm; mobile phase: [water (0.05%NH₄OH)-ACN]; B %: 40-70%, 9 min) to give the product (47.66 mg, 0.12mmol, 25% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.54 (d, 1H),8.24 (d, 1H), 8.09 (dd, 1H), 7.57 (d, 1H), 5.11 (s, 2H), 3.53 (s, 3H),1.90 (s, 6H). LCMS R_(t)=1.21 min in 2.0 min chromatography, 10-80AB, MSESI calcd. for C₁₆H₁₆F₄N₅O₂ [M+H]⁺ 386.1, found 386.0.

Example 27:6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A33: To a solution of (5-bromo-2-pyridyl)hydrazine (8.5 g,45.21 mmol) in toluene (80 mL), was added 2-methoxyacetyl chloride (5.4g, 49.73 mmol) dropwise at 25° C. The solution was stirred at 25° C. for30 min, then refluxed at 120° C. for 48 hours. After cooling to roomtemperature, the reaction mixture was concentrated to give a residue.The residue was triturated from DCM (100 mL) the yield the product (3.0g, 10.01 mmol, 22% yield) as a solid. ¹H NMR (MeOD-d₄, 400 MHz) δ=9.15(s, 1H), 8.19-8.32 (m, 1H), 8.11-7.96 (m, 1H), 5.09 (s, 2H), 3.49 (s,3H).

Synthesis of Compound 28: A mixture of6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (150 mg, 0.62mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(259.61 mg, 0.74 mmol), K₂CO₃ (171.29 mg, 1.24 mmol), Pd(dppf)Cl₂ (68.01mg, 0.09 mmol) in mixed solvents 1,4-Dioxane (15 mL) and Water (3 mL)was heated at 85° C. for 16 hours. After cooling to room temperature,the reaction was concentrated and diluted with H₂O (20 mL), thenextracted with DCM (20 mL×2). The combined organic phase was washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified using Prep-HPLC (YMC-ActusTriart C18 (100 mm×30 mm, 5 μm) A=H₂O (0.05% HCl) and B=CH₃CN; 50-75% Bover 8 minutes) yielding the product in CH₃CN/H₂O (˜150 mL). Thesolution was concentrated to remove most of the CH₃CN, basified withNaHCO₃(solid) to pH-9, then extracted with DCM (50 mL×3). The combinedorganic phase was concentrated yielding the product (121.16 mg, 0.32mmol, 51% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ=8.34 (s, 1H),8.16 (d, 1H), 7.89 (d, 1H), 7.60 (dd, 1H), 7.47 (dd, 1H), 5.08 (s, 2H),3.42 (s, 3H), 1.87 (s, 6H). LCMS R_(t)=1.25 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₇F₄N₄O₂ [M+H]⁺ 385.1,found 384.9.

Example 28:6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine

A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine(150 mg, 0.62 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(238.75 mg, 0.74 mmol), K₂CO₃ (171.29 mg, 1.24 mmol), Pd(dppf)Cl₂ (68.01mg, 0.09 mmol) in mixed solvents 1,4-Dioxane (15 mL) and Water (3 mL)was stirred at 85° C. for 16 hours. After cooling to room temperature,the reaction was concentrated and diluted with H₂O (20 mL), thenextracted with DCM (20 mL×2). The combined organic phase was washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-HPLC ((BostonPrime C18 (150 mm×30 mm, 5μ.m) A=H₂O (0.05% NH₄OH) and B=CH₃CN; 40-70% Bover 8 minutes) to give the product (141.29 mg, 0.39 mmol, 64% yield) asa solid. ¹H NMR (CDCl₃, 400 MHz) δ=8.35 (s, 1H), 8.17 (d, 1H), 7.90 (d,1H), 7.65 (dd, 1H), 7.47 (dd, 1H), 5.09 (s, 2H), 4.91 (q, 2H), 3.43 (s,3H). LCMS R_(t)=1.17 min in 2.0 min chromatography, 10-80AB, MS ESIcalcd. for C₁₅H₁₃F₄N₄O₂ [M+H]⁺ 357.1, found 356.9.

Example 29:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70mg, 250 μmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(97 mg, 300 μmol), K₂CO₃ (69.59 mg, 0.50 mmol) and Pd(dppf)Cl₂ (27.63mg, 0.04 mmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at80° C. for 12 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (10mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was first purified byPrep-HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H₂O (0.05% NH₄OH)and B=CH₃CN; 43-73% B over 8 minutes), then followed by Prep-HPLC(Boston Green ODS (150 mm×30 mm, 5 μm), A=H₂O (0.075% TFA) and B=CH₃CN;49-63% B over 10 minutes). The combined fractions were concentrated toremove ACN, and basified with sat. NaHCO₃ to pH˜8, and the mixture wasextracted with EtOAc (30 mL×2). The combined organic phase was washedwith brine (40 mL), dried over Na₂SO₄, filtered and concentrated to givethe product (41.36 mg, 105.4 μmol, 42% yield) as a solid. ¹H NMR(DMSO-d₆, 400 MHz) δ_(H)=8.74 (s, 1H), 8.47 (d, 1H), 8.36 (dd, 1H), 8.11(dd, 1H), 7.96 (dd, 1H), 5.18 (q, 2H), 3.89 (s, 3H). LCMS R_(t)=1.19 minin 2.0 min chromatography, 10-80AB, MS ESI calcd. C₁₅H₁₁F₆N₄O₂ [M+H]⁺393.1, found 393.0.

Example 30:6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine(70 mg, 0.35 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(141.73 mg, 0.42 mmol), Cs₂CO₃ (229.66 mg, 0.70 mmol), Pd(dppf)Cl₂(38.68 mg, 0.05 mmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL) wasstirred at 70° C. for 5 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (20 mL) and extracted withEtOAc (30 mL×2). The combined organic phase was washed with water (30mL) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was first purified by Prep-TLC(silica gel, PE:EtOAc=1:1). The resulting product was further purifiedby Prep-HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm),A=H₂O (0.05% NH₄OH)and B=CH₃CN; 38-68% B over 9 minutes), to give the product (4.43 mg,11.9 μmol, 3% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=9.44 (d,1H), 8.49 (dd, 1H), 8.47 (s, 1H), 8.05 (dd, 1H), 5.95-5.83 (m, 1H), 5.14(s, 2H), 3.47 (s, 3H), 1.60 (d, 3H). LCMS R_(t)=1.18 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. C₁₅H₁₄F₄N₅O₂ [M+H]⁺ 372.1, found371.9.

Example 31:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100mg, 0.34 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(137.67 mg, 0.41 mmol), K₂CO₃ (94.64 mg, 0.68 mmol) and Pd(dppf)Cl₂(37.58 mg, 0.05 mmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL) wasstirred at 80° C. for 12 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (10 mL), and extractedwith EtOAc (20 mL×2). The combined organic phase was washed with water(10 mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 (150 mm×30 mm, Sum), A=H₂O (0.05% NH₄OH) and B=CH₃CN;60-90% B over 9 minutes) to give the product (39.75 mg, 93.5 μmol, 27%yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.72 (s, 1H), 8.44(d, 1H), 8.33 (dd, 1H), 8.10 (d, 1H), 7.94 (dd, 1H), 6.02 (spt, 1H),4.29 (q, 2H), 1.54 (d, 3H), 1.36 (t, 3H). LCMS R_(t)=1.28 min in 2.0 minchromatography, 10-80ABMS ESI calcd. C₁₇H₁₅F₆N₄O₂ [M+H]⁺ 421.1, found421.0.

Example 32:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(200 mg, 0.49 mmol) and AgOTf (1.25 g, 4.86 mmol) in Ethanol (10 mL) andMeCN (10 mL) was stirred at 90° C. for 5 days. The mixture was cooled toroom temperature. EtOAc (50 mL) and brine (50 mL) were added to themixture, and the mixture was filtered through Celite. The filtrate wasseparated and the aqueous layer was extracted with EtOAc (50 mL). Thecombined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=10% to 30% to 50%)and then triturated from n-hexane (5 mL) to give the product (41.27 mg,98.0 μmol, 20% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=9.52 (d,1H), 8.50-8.45 (m, 2H), 8.04 (dd, 1H), 6.00-5.82 (m, 1H), 4.37 (q, 2H),1.60 (d, 3H), 1.51 (t, 3H). LCMS R_(t)=1.29 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₆H₁₄F₆N₅O₂ [M+H]⁺ 422.1,found 422.0.

Example 33:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(126.2 mg, 0.38 mmol), Pd(dppf)Cl₂ (37.58 mg, 0.05 mmol),6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100mg, 0.34 mmol) and K₂CO₃ (94.64 mg, 0.68 mmol) in 1,4-Dioxane (5 mL) andWater (1 mL) was stirred at 90° C. for 16 hours under N₂. After coolingto room temperature, the mixture was filtered through Celite, and elutedwith EtOAc (10 mL×2), and the filtrate was concentrated to give thecrude product. The crude product was purified by Prep-HPLC (Boston PrimeC18 (150 mm×30 mm, 5 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN; 45-75% B over9 minutes) to give the product (62.87 mg, 0.15 mmol, 43% yield) as asolid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.72 (s, 1H), 8.44 (d, 1H), 8.33(dd, 1H), 8.14-8.06 (m, 1H), 7.94 (dd, 1H), 6.01 (spt, 1H), 4.28 (q,2H), 1.54 (d, 3H), 1.36 (t, 3H). LCMS R_(t)=1.26 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₅F₆N₄O₂ [M+H]⁺ 421.1,found 421.0.

Example 34:6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine(100 mg, 0.50 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(194 mg, 0.60 mmol), K₃PO₄ (213.79 mg, 1.01 mmol) and Pd(t-Bu₃P)₂ (38.6mg, 0.08 mmol) in 1,4-Dioxane (10 mL) and Water (1 mL) was stirred at80° C. under N₂ for 3 hours. After cooling to room temperature, water(20 mL) and EtOAc (20 mL) were added to the mixture and the mixture wasfiltered through Celite. After separating, the organic phase was washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby Prep-HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm) A=H₂O (0.05% NH₄OH)and B=CH₃CN; 33-63% B over 8 minutes) to give the product (49 mg, 137.2μmol, 27% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.54 (d, 1H),8.25 (d, 1H), 8.17 (dd, 1H), 7.58 (d, 1H), 5.11 (s, 2H), 4.94 (q, 2H),3.54 (s, 3H). LCMS R_(t)=1.08 min in 2.0 min chromatography, 10-80AB, MSESI calcd. for C₁₄H₁₂F₄N₅O₂ [M+H]⁺ 358.1, found 357.9.

Example 35:3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(121.22 mg, 0.36 mmol), Pd(dppf)Cl₂ (36.09 mg, 0.05 mmol),6-bromo-3-[cyclopropoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine(100 mg, 0.33 mmol) and K₂CO₃ (90.9 mg, 0.66 mmol) in 1,4-Dioxane (5 mL)and water (1 mL) was stirred at 90° C. for 16 hours under N₂. Aftercooling to room temperature, the mixture was filtered through Celite,and eluted with EtOAc (10 mL×2), and the filtrate was concentrated togive the crude product. The crude product was purified by Prep-HPLC(Boston Prime C18 (150 mm×30 mm, 5 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN;47-77% B over 9 minutes) to give the product (54.98 mg, 0.13 mmol, 39%yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.65 (s, 1H), 8.44(d, 1H), 8.33 (dd, 1H), 8.11 (d, 1H), 7.94 (dd, 1H), 6.07-5.97 (m, 1H),4.25-4.15 (m, 1H), 1.54 (d, 3H), 0.95-0.86 (m, 2H), 0.77-0.69 (m, 2H).LCMS R_(t)=1.33 min in 2.0 min chromatography, 10-80ABMS ESI calcd. forC₁₈H₁₅F₆N₄O₂ [M+H]⁺ 433.1, found 433.1.

Example 36:3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A36: To a mixture of cyclopropanol (246.74 mg, 4.25 mmol),6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (600mg, 2.12 mmol) in DMF (10 mL) was added potassium tert-butoxide (476.69mg, 4.25 mmol). The reaction mixture was stirred at 20° C. for 2 hours.The reaction was quenched with sat. NH₄Cl (40 mL), then the mixture wasextracted with EtOAc (50 mL×2). The combined organic phase was washedwith water (80 mL) and brine (80 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 20% to 40%) togive the product (270 mg, 0.89 mmol, 42% yield) as a solid. LCMSR_(t)=3.74 min in 7.0 min chromatography, 0-60ABMS ESI calcd.C₁₀H₉BrF₂N₃O [M+H+2]⁺306.0, found 305.8.

Synthesis of Compound 37: A mixture of6-bromo-3-[cyclopropoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine(100 mg, 0.33 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(132.24 mg, 0.39 mmol), K₂CO₃ (90.9 mg, 0.66 mmol) and Pd(dppf)Cl₂(36.09 mg, 0.05 mmol) in 1,4-Dioxane (5 mL) and water (0.50 mL) wasstirred at 80° C. for 12 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (10 mL), and the mixturewas extracted with EtOAc (20 mL×2). The combined organic phase waswashed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by Prep-HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H₂O(0.05% NH₄OH) and B=CH₃CN; 50-70% B over 9 minutes) to give the product(35.99 mg, 83.2 μmol, 25% yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz)δ_(H)=8.65 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.11 (dd, 1H), 7.94(dd, 1H), 6.09-5.95 (m, 1H), 4.25-4.14 (m, 1H), 1.54 (d, 3H), 0.95-0.86(m, 2H), 0.79-0.67 (m, 2H). LCMS R_(t)=1.29 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. C₁₈H₁₅F₆N₄O₂ [M+H]⁺ 433.1, found433.0.

Example 37:6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A37: To a mixture of 1,1,2-trimethoxyethane (1.25 g, 10.38mmol) and (5-chloropyrazin-2-yl)hydrazine (1 g, 6.92 mmol) in Ethanol(20 mL) was added 12N HCl (1.73 mL, 20.75 mmol), then the mixture wasstirred at 20° C. for 20 hours. To the mixture was added water (20 mL),then basified with Na₂CO₃ (solid) to pH 9 and extracted with EtOAc (50mL×4). The combined organic phase was washed with brine (30 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was triturated from EtOAc/PE (2/10 mL) and dried in oven,yielding 5-chloro-N-(2-methoxyethylideneamino)pyrazin-2-amine (1050 mg,3.73 mmol, 54% yield) as a solid. LCMS R_(t)=0.70 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for C₇H₁₀ClN₄O [M+H]⁺ 201.0, found201.0.

Synthesis of A38: To a mixture of5-chloro-N-(2-methoxyethylideneamino)pyrazin-2-amine (1 g, 4.98 mmol) inDMF (10 mL) was added a solution of NB S (1.24 g, 6.98 mmol) in DMF (7mL) dropwise over 0.5 hour, then the mixture was stirred at 20° C. for 1hour. The mixture was diluted with H₂O (50 mL) and extracted with EtOAc(50 mL×4). The combined organic phase was washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product(1000 mg, 3.58 mmol, 72% yield) as a solid, which was used directlywithout any further purification. LCMS R_(t)=0.80 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for C₇H₉BrClN₄O [M+H+2]⁺ 281.0,found 280.9.

Synthesis of A34: To a mixture ofN-(5-chloropyrazin-2-yl)-2-methoxy-ethanehydrazonoyl bromide (1 g, 3.58mmol) in Toluene (15 mL) was added Et₃N (0.99 mL, 7.16 mmol), then themixture was stirred at 20° C. for 1 hour. The mixture was diluted withH₂O (30 mL), and extracted with EtOAc (50 mL×2). The combined organicphase was washed with water (20 mL×2) and brine (20 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 40% to 80%) to give the product (380 mg, 1.87 mmol, 52% yield)as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=9.21 (d, 1H), 8.28 (d, 1H),5.07 (s, 2H), 3.45 (s, 3H). LCMS R_(t)=0.30 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for C₇H₈ClN₄O [M+H]⁺ 199.0, found199.0.

Synthesis of Compound 38: A mixture of6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(177.16 mg, 0.53 mmol), Pd(dppf)Cl₂ (64.47 mg, 88.1 μmol) and Cs₂CO₃(229.66 mg, 0.70 mmol) in 1,4-Dioxane (8 mL) and Water (0.80 mL) wasstirred at 75° C. for 12 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (30 mL), and the mixturewas extracted with EtOAc (50 mL×2). The combined organic phase waswashed with water (20 mL×2) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas first purified by Prep-TLC (silica gel, PE:EtOAc=1:1), followed byprep-HPLC [Boston Prime C18 (150 mm×30 mm, 5 μm) A=H2O (0.05% NH₄OH) andB=CH₃CN; 38-68% B over 9 minutes],to give the product (12.63 mg, 34.0μmol, 10% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=9.44 (d, 1H),8.50 (d, 1H), 8.47 (d, 1H), 8.05 (dd, 1H), 5.97-5.84 (m, 1H), 5.14 (s,2H), 3.47 (s, 3H), 1.60 (d, 3H). LCMS R_(t)=1.17 min in 2.0 minchromatography, 10-80ABMS ESI calcd. for C₁₅H₁₄F₄N₅O₂ [M+H]⁺ 372.1,found 371.9.

Example 38:6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine(70 mg, 0.35 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(169.75 mg, 0.53 mmol), Pd(dppf)Cl₂ (64.47 mg, 88.1 μmol) and Cs₂CO₃(229.66 mg, 0.70 mmol) in 1,4-Dioxane (8 mL) and water (0.80 mL) wasstirred at 75° C. for 12 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (20 mL), and the mixturewas extracted with EtOAc (30 mL×2). The combined organic phase waswashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product(14.65 mg, 40.7 μmol, 12% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=9.44 (d, H), 8.52 (d, 1H), 8.48 (d, 1H), 8.07 (dd, 1H), 5.14 (s,2H), 4.92 (q, 2H), 3.47 (s, 3H). LCMS R_(t)=1.19 min in 2.0 minchromatography, 10-80ABMS ESI calcd. for C₁₄H₁₂F₄N₅O₂ [M+H]⁺ 358.1,found 357.9.

Example 39:6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine

A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine(200 mg, 0.83 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(332.23 mg, 0.99 mmol), K₂CO₃ (228.38 mg, 1.65 mmol), Pd(dppf)Cl₂ (90.68mg, 0.12 mmol) in 1,4-dioxane (15 mL) and Water (5 mL) 85° C. for 16hours. After cooling to room temperature, the reaction was concentratedand diluted with H₂O (20 mL), then extracted with DCM (20 mL×2). Thecombined organic phase was washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified using Prep-HPLC (Boston Prime C18 (150 mm×30 mm 5μ.m) A=H₂O(0.05% NH₄OH) and B=CH₃CN; 35-65% B over 9 minutes) to give the product(104.44 mg, 0.28 mmol, 34% yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz)δ_(H)=8.85 (s, 1H), 8.49 (d, 1H), 8.35 (dd, 1H), 7.89-8.05 (m, 1H),7.77-7.88 (m, 1H), 6.05-5.87 (m, 1H), 5.02 (s, 2H), 3.35 (s, 3H), 1.55(d, 3H). LCMS R_(t)=1.150 min in 2.0 min chromatography, 10-80AB, MS ESIcalcd. for C₁₆H₁₅F₄N₄O₂ [M+H]⁺ 371.1, found 371.1.

Example 40:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine(300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in ethanol (10 mL)and MeCN (10 mL) was stirred at 90° C. for 9 days. After cooling to roomtemperature, the reaction was diluted with EtOAc (60 mL), and themixture was added with brine (20 mL). The mixture was filtered throughCelite and extracted with EtOAc (50 mL×2). The combined organic layerwas washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to70. The iproduct was then triturated from n-Hexane (1 mL) and i-Pr₂O (1mL), to give the product (28.86 mg, 67.3 μmol, 9% yield) as a solid. ¹HNMR (CDCl₃, 400 MHz) δ_(H)=8.54 (d, 1H), 8.29 (d, 1H), 8.13 (dd, 1H),7.65 (d, 1H), 5.92 (spt, 1H), 4.33 (q, 2H), 1.61 (d, 3H), 1.48 (t, 3H).LCMS R_(t)=1.27 min in 2.0 min chromatography, 10-80AB, MS ESI calcd.C₁₆H₁₄F₆N₅O₂ [M+H]⁺ 422.1, found 422.0.

Example 41:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A26-a: A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(1.54 g, 4.6 mmol),6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (1g, 4.18 mmol), Pd(t-Bu₃P)₂ (320.73 mg, 0.63 mmol) and K₃PO₄ (1.78 g,8.37 mmol) in 1,4-Dioxane (20 mL) and water (4 mL) was stirred at 80° C.for 16 hours under N₂. After cooling to room temperature, the mixturewas filtered through Celite, and eluted with EtOAc (20 mL×2), and thefiltrate was concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=30% to60%) to give the product (1000 mg, 2.12 mmol, 51% yield) as a solid.LCMS R_(t)=0.93 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. forC₁₄H₉ClF₆N₅O [M+H]⁺ 412.0, found 412.1.

Synthesis of Compound 42: A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine(300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in ethanol (10 mL,0.73 mmol) and CH₃CN (10 mL) was stirred at 90° C. for 8 days. Aftercooling to room temperature, the reaction was diluted with EtOAc (40mL), and the mixture was added to saturated NaCl (40 mL), the mixturewas filtered through Celite, and eluted with EtOAc (20 mL×2), and thefiltrate was concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to50% to 100%). The product was further purified by Prep-HPLC (BostonPrime C18 (150 mm×30 mm 5 μm) A=H₂O (0.05% NH₄OH v/v) and B=CH₃CN;51-81% B over 9 minutes), to give the product (8.12 mg, 19.3 μmol, 3%yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.54 (d, 1H), 8.30 (d,1H), 8.13 (dd, 1H), 7.66 (d, 1H), 5.96-5.88 (m, 1H), 4.33 (q, 2H), 1.62(s, 3H), 1.48 (t, 3H). LCMS R_(t)=1.29 min in 2.0 min chromatography,10-80AB, MS ESI calcd. for C₁₆H₁₄F₆N₅O₂ [M+H]⁺ 422.1, found 422.0.

Example 42:6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine

A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine(100 mg, 0.41 mmol), Pd(dppf)Cl₂ (45.34 mg, 0.06 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(166.12 mg, 0.50 mmol) and K₂CO₃ (114.19 mg, 0.83 mmol) in 1,4-Dioxane(5 mL) and water (1 mL) was stirred at 80° C. for 16 hours under N₂.After cooling to room temperature, the mixture was filtered throughCelite, and eluted with EtOAc (10 mL×2), and the filtrate wasconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=50% to 100%). Theproduct was then triturated from n-hexane/DCM (5:1, 10 mL) to give theproduct (46.5 mg, 0.13 mmol, 30% yield) as a solid. ¹H NMR (DMSO-d₆, 400MHz) δ_(H)=8.84 (s, 1H), 8.49 (d, 1H), 8.35 (dd, 1H), 7.97-7.90 (m, 1H),7.87-7.80 (m, 1H), 6.01 (spt, 1H), 5.01 (s, 2H), 3.34 (s, 3H), 1.54 (d,3H). LCMS R_(t)=1.13 min in 2.0 min chromatography, 10-80AB, MS ESIcalcd. for C₁₆H₁₅F₄N₄O₂ [M+H]⁺ 371.1, found 370.9.

Example 43:6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine(100 mg, 0.50 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(202.47 mg, 0.60 mmol), K₃PO₄ (213.79 mg, 1.01 mmol) and Pd(t-Bu₃P)₂(38.6 mg, 0.08 mmol) in 1,4-Dioxane (10 mL) and water (1 mL) was stirredat 80° C. under N₂ for 3 hours. After cooling to room temperature, water(20 mL) and EtOAc (20 mL) was added to the mixture and filtered throughCelite. After separating, the organic phase was washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-HPLC (Boston PrimeC18 (150 mm×30 mm, 5 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN; 33-63% B over8 minutes) to give the product (38 mg, 102.3 μmol, 20% yield) as asolid. ⁺H NMR (CDCl₃, 400 MHz) δ_(H)=8.53 (d, 1H), 8.25 (d, 1H), 8.14(dd, 1H), 7.57 (d, 1H), 5.98-5.85 (m, 1H), 5.11 (s, 2H), 3.54 (s, 3H),1.61 (d, 3H). LCMS R_(t)=1.13 min in 2.0 min chromatography, 10-80AB, MSESI calcd. for C₁₅H₁₄F₄N₅O₂ [M+H]⁺ 372.1, found 371.9.

Example 44:3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(200 mg, 0.49 mmol) and AgOTf (1.25 g, 4.86 mmol) in Isobutyl alcohol(10 mL) and MeCN (10 mL) was stirred at 90° C. for 7 days. The EtOAc (50mL) and brine (50 mL) were added to the mixture and some solid wasobserved. The mixture was filtered through Celite. The filtrate wasseparated and the aqueous layer was extracted with EtOAc (50 mL). Thecombined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=10% to 30% to 50%) togive the product (80 mg) as an oil.

The impure product (80 mg, 0.18 mmol) was purified by Prep-HPLC (BostonGreen ODS (150 mm×30 mm, 5 μm) A=H₂O (0.075% TFA) and B=CH₃CN; 66-96% Bover 8 minutes) and concentrated to give a residue. To the residue wasadded saturated aqueous NaHCO₃ (10 mL), and the mixture was extractedwith EtOAc (15 mL×2). The combined organic phase was washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to givethe product (55.97 mg, 124.6 μmol, 70% yield) as a solid. ¹H NMR(CDCl₃+D₂O, 400 MHz) δ_(H)=9.52 (d, 1H), 8.53-8.43 (m, 2H), 8.04 (dd,1H), 5.98-5.84 (m, 1H), 4.06 (d, 2H), 2.21-2.06 (m, 1H), 1.60 (d, 3H),1.08 (d, 6H). LCMS R_(t)=1.37 min in 2.0 min chromatography, 10-80AB, MSESI calcd. for C₁₈H₁₈F₆N₅O₂ [M+H]⁺ 450.1, found 450.0.

Example 45:6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A32: To a solution of (6-chloropyridazin-3-yl)hydrazine (3g, 20.75 mmol) in Toluene (80 mL) was added 2-methoxyacetyl chloride(2.48 g, 22.83 mmol) dropwise at 25° C. The solution was stirred at 25°C. for 30 min, and refluxed at 120° C. for 24 hours. After cooling toroom temperature, the mixture was diluted with H₂O (40 mL) and extractedwith EtOAc (40 mL×2). The combined organic phase was washed with brine(40 mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was triturated from i-Pr₂O (10 mL), to givethe product (1500 mg, 7.31 mmol, 35% yield) as a solid. LCMS R_(t)=0.43min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₇H₈ClN₄O[M+H]⁺ 198.0, found 199.0.

Synthesis of Compound 46: A mixture of6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.5mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(202.47 mg, 0.6 mmol), K₃PO₄ (213.79 mg, 1.01 mmol), Pd(t-Bu₃P)₂ (38.6mg, 0.08 mmol) in 1,4-Dioxane (5 mL) and water (0.5 mL) was stirred at80° C. for 12 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL×2).The combined organic phase was washed with water (10 mL) and brine (10mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by Prep-HPLC (column: BostonPrime (150 mm×30 mm, 5 μm; mobile phase: A=H₂O (0.05% NH₄OH); B=CH₃CN,35-65% B over 9 min) to give the product (43.29 mg, 0.12 mmol, 23%yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.53 (d, 1H), 8.25 (d,1H), 8.14 (dd, 1H), 7.57 (d, 1H), 5.98-5.5.85 (m, 1H), 5.11 (s, 2H),3.54 (s, 3H), 1.61 (d, 3H). LCMS R_(t)=1.17 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₅H₁₄F₄N₅O₂ [M+H]⁺ 372.1,found 372.1.

Example 46:3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine(300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in2-methylpropan-1-ol (10 mL, 0.73 mmol) and MeCN (10 mL) was stirred at90° C. for 9 days. After cooling to room temperature, the reaction wasdiluted with EtOAc (60 mL) and brine (20 mL), filtered through Celite,and extracted with EtOAc (50 mL×2). The combined organic layer waswashed with water (50 mL) and brine (50 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 70%)The isolated product was further purified by Prep-HPLC (Boston Prime C18(150 mm×30 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN; 60-90% B over 9minutes) to give the product (7.42 mg, 16.5 μmol, 2% yield) as a solid.¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.54 (d, 1H), 8.30 (d, 1H), 8.14 (dd, 1H),7.66 (d, 1H), 5.98-5.85 (m, 1H), 4.01 (d, 2H), 2.15-2.01 (m, 1H), 1.61(d, 3H), 1.05 (d, 6H). LCMS R_(t)=1.39 min in 2.0 min chromatography,10-80AB, MS ESI calcd. C₁₈H₁₈F₆N₅O₂ [M+H]⁺ 450.1, found 450.1.

Example 47:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine(150 mg, 0.76 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(527.36 mg, 1.51 mmol), Cs₂CO₃ (738.18 mg, 2.27 mmol), Pd(dppf)Cl₂(110.52 mg, 0.15 mmol) in 1,4-Dioxane (8 mL) and water (0.80 mL) wasstirred at 75° C. for 9 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (20 mL), and the mixturewas extracted with EtOAc (30 mL×2). The combined organic phase waswashed with water (30 mL×1) and brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H₂O(0.05% NH₄OH) and B=CH₃CN; 49-59% B over 9 minutes) to give the product(90.56 mg, 235 μmol, 31% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=9.43 (s, 1H), 8.57-8.40 (m, 2H), 8.01 (d, 1H), 5.13 (s, 2H), 3.46(s, 3H), 1.88 (s, 6H). LCMS R_(t)=1.24 min in 2.0 min chromatography,10-80AB, MS ESI calcd. C₁₆H₁₆F₄N₅O₂ [M+H]⁺ 386.1 found 386.1

Example 48:3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine(500 mg, 1.21 mmol) and AgOTf (3120.6 mg, 12.15 mmol) in2-methylpropan-1-ol (10 mL, 1.21 mmol) and CH₃CN (10 mL) was stirred at90° C. for 8 days. After cooling to room temperature, the reaction wasdiluted with EtOAc (40 mL), and the mixture was added with brine (40mL), the mixture was filtered through Celite, and eluted with EtOAc (20mL×2), and the filtrate was concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 50% to 100%) to give the impure product. The impure productwas purified by Prep-HPLC (Waters Xbridge 150 mm×25 mm, 5 μm) A=H₂O (10mM NH₄HCO₃) and B=CH₃CN; 54-84% B over 8 minutes) to give the product(53.85 mg, 0.12 mmol, 10% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=8.54 (d, 1H), 8.30 (d, 1H), 8.13 (dd, 1H), 7.66 (d, 1H), 5.92(spt, 1H), 4.01 (d, 2H), 2.16-2.04 (m, 1H), 1.61 (d, 3H), 1.05 (d, 6H).LCMS R_(t)=1.42 min in 2.0 min chromatography, 10-80AB, MS ESI calcd.for C₁₈H₁₈F₆N₅O₂ [M+H]⁺ 450.1, found 450.1.

Example 49:3-(ethoxymethyl)-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A40: A mixture of[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]hydrazine(200 mg, 0.63 mmol), DIPEA (0.33 mL, 1.89 mmol), and 2-ethoxyacetylchloride (92.71 mg, 0.76 mmol) in CH₂Cl₂ (10 mL) was stirred at 25° C.for 16 hours. The mixture was concentrated to the residue, and theresidue was re-dissolved in EtOAc (20 mL), washed with water (10 mL×2),brine (10 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedto give the product (150 mg, 0.13 mmol, 20% yield) as a solid. LCMSR_(t)=0.84 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. forC₁₆H₁₈F₄N₅O₃ [M+H]⁺ 404.1, found 404.2.

Synthesis of Compound 50: To a mixture of2-ethoxy-N′-[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]acetohydrazide(150 mg, 0.37 mmol) in Acetic acid (15 mL) was stirred at 120° C. for 4days. After cooling to room temperature, the mixture was concentratedyielding a solid. The solid was re-dissolved in EtOAc (20 mL), basifiedwith sat. Na₂CO₃ to pH 9, washed with water (10 mL×2), brine (10 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by Prep-HPLC (Boston Prime C18150 mm×30 mm 5 μm) A=H₂O (0.05% ammonia hydroxide) and B=CH₃CN; 45-75% Bover 9 minutes) to give the product (48.08 mg, 0.12 mmol, 34% yield) asa solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=9.55 (d, 1H), 9.15 (d, 1H),8.77 (d, 1H), 8.49 (dd, 1H), 6.08-5.98 (m, 1H), 5.08 (s, 2H), 3.61 (q,2H), 1.55 (d, 3H), 1.15 (t, 3H). LCMS R_(t)=1.23 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₆H₁₆F₄N₅O₂ [M+H]⁺ 386.1,found 386.0.

Example 50:3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of cyclopropanol (28.22 mg, 0.49 mmol),3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(100 mg, 0.24 mmol) in DMF (2 mL) was added potassium tert-butoxide(54.51 mg, 0.49 mmol) dropwise. The reaction mixture was stirred at 20°C. for 2 hours. The reaction was quenched with saturated NH₄Cl (10 mL),and the mixture was extracted with EtOAc (10 mL×2). The combined organicphase was washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃)and B=CH₃CN; 57-67% B over 8 minutes) to give the product (3.98 mg, 0.01mmol, 4% yield) as an oil. ¹H NMR (CD₃CN, 400 MHz) δ_(H)=9.46 (s, 1H),8.67-8.56 (m, 2H), 8.20 (dd, 1H), 6.01-5.92 (m, 1H), 4.21-4.14 (m, 1H),1.58 (d, 3H), 1.00-0.91 (m, 2H), 0.81-0.73 (m, 2H). LCMS R_(t)=1.31 minin 2 min chromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₄F₆N₅O₂ [M+H]⁺434.1, found 433.9.

Example 51:3-(ethoxymethyl)-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A41: To a mixture of (5-chloropyrazin-2-yl)hydrazine (500mg, 3.46 mmol) and 2-ethoxyacetyl chloride (551.03 mg, 4.5 mmol) inToluene (7 mL) was stirred at 20° C. for 2 hours then heated to 130° C.for 3 days. Then most of the toluene was removed, and Acetic acid (40mL) was added and and stirred at 120° C. for 16 hours. After cooling toroom temperature, the mixture was concentrated to give a residue. Theresidue was re-dissolved in EtOAc (40 mL), basified with saturatedNa₂CO₃ to pH 9, washed with water (20 mL×2), brine (20 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=40% to 70%), to give the product (240 mg, 1.11 mmol, 32%yield) as a solid. LCMS R_(t)=0.60 min in 1.5 min chromatography,5-95AB, MS ESI calcd. for C₈H₁₀ClN₄O [M+H]⁺ 213.0, found 213.0.

Synthesis of Compound 52: A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(453.86 mg, 1.35 mmol), Cs₂CO₃ (1103.16 mg, 3.39 mmol),6-chloro-3-(ethoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (240 mg, 1.13mmol) and Pd(dppf)Cl₂ (123.88 mg, 0.17 mmol) in 1,4-Dioxane (10 mL) andwater (2 mL) was stirred at 75° C. for 16 hours under N₂. After coolingto room temperature, the mixture was filtered through Celite, and elutedwith EtOAc (10 mL×2), and the filtrate was concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=30% to 60% to 100%) to give the impure product.The impure product was purified by Prep-HPLC (Waters Xbridge 150 mm×25mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 40-70% B over 8 minutes) togive the product (37.8 mg, 98.1 μmol, 9% yield) as a solid. ¹H NMR(DMSO-d₆, 400 MHz) δ_(H)=9.56 (d, 1H), 9.15 (d, 1H), 8.77 (d, H), 8.49(dd, 1H), 6.09-5.97 (m, 1H), 5.08 (s, 2H), 3.61 (q, 2H), 1.55 (d, 3H),1.14 (t, 3H). LCMS R_(t)=1.24 min in 2.0 min chromatography, 10-80AB, MSESI calcd. for C₁₆H₁₆F₄N₅O₂ [M+H]⁺ 386.1, found 386.1.

Example 52:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A19-a: A mixture of 2-bromo-5-chloro-pyrazine (3 g, 15.51mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(4.98 g, 15.51 mmol), Cs₂CO₃ (10.11 g, 31.02 mmol) and Pd(dppf)Cl₂ (1.7g, 2.33 mmol) in 1,4-Dioxane (50 mL) and water (5 mL) was stirred at 55°C. under N₂ for 5 hours. The reaction was cooled to room temperature andconcentrated to give a residue. To the residue was added water (50 mL)and EtOAc (50 mL) and then the mixture was filtered. After separation,the organic phase was washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by chromatography flash on silica gel (EtOAc inPE=0% to 5% to 10%) to give the product (3700 mg, 10.69 mmol, 69% yield)as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=9.19 (d, 1H), 8.88 (d, 1H),8.80 (d, 1H), 8.49 (dd, 1H), 5.18 (q, 2H). LCMS R_(t)=0.93 min in 1.5min chromatography, 5-95AB, MS ESI calcd. for C₁₁H₁₇ClF₄N₃O [M+H]⁺308.0, found 308.0.

Synthesis of A20-a: To a mixture of2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (3.7g, 12.03 mmol) in MeCN (50 mL) was added hydrazine (3.85 g, 120.27mmol), and the mixture was stirred at 90° C. for 16 hours. The reactionwas cooled to room temperature and concentrated to give a residue. Water(30 mL) was added to the residue and extracted with EtOAc (30 mL×2). Thecombined organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give the crude product(3500 mg, 9.60 mmol, 80% yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz)δ_(H)=8.62 (d, 1H), 8.58 (d, 1H), 8.30-8.24 (m, 2H), 8.19 (d, 1H), 5.12(q, 2H), 4.36 (s, 2H). LCMS R_(t)=0.73 min in 1.5 min chromatography,5-95AB, MS ESI calcd. for C₁₁H₁₀F₄N₅O [M+1H]⁺ 304.1, found 304.0.

Synthesis of A18: A solution of[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine(3 g, 9.89 mmol) and (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (7.21 g, 29.68 mmol) in Toluene (60 mL)was stirred at 110° C. for 96 hours, Then to the mixture was addedmolecular sieves (3 g), and the mixture was stirred at 130° C. foranother 16 hours. After cooling to room temperature, the mixture wasconcentrated to give a residue. To the residue was added water (20 mL),extracted with EtOAc (30 mL×2). The combined organic phase was washedwith water (20 mL), brine (20 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography column on silica gel (EtOAc inPE=0% to 10% to 20%) to give the product (1300 mg, 3.24 mmol, 33% yield)as an oil. LCMS R_(t)=2.63 min in 4 min chromatography, 10-80AB, MS ESIcalcd. for C₁₃H₇ClF₆N₅O [M+H]⁺ 398.0, found 397.9.

Synthesis of Compound 53: A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(600 mg, 1.51 mmol) and AgOTf (3.88 g, 15.09 mmol), in Methanol (12 mL)and DMF (4 mL) was stirred at 90° C. for 48 hours. After cooling to roomtemperature, the reaction mixture was treated with brine (20 mL), andthe precipitate was filtrated. The filtrate was concentrated and dilutedwith water (20 mL), then extracted with EtOAc (20 mL×3). The combinedorganic phase was washed with brine (20 mL), dried over Na₂SO₄ andconcentrated to give a crude product. The crude product was purified byflash chromatography on silica gel (EtOAc in PE=0% to 10% to 30%) togive the product (247.53 mg, 0.63 mmol, 42% yield) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=9.52 (d, 1H), 8.52 (d, 1H), 8.46 (d, 1H), 8.07(dd, 1H), 4.93 (q, 2H), 3.98 (s, 3H). LCMS R_(t)=1.23 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for C₁₄H₁₀F₆N₅O₂ [M+H]⁺ 394.1,found 394.0.

Example 53:3-[difluoro(methoxy)methyl]-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of3-[chloro(difluoro)methyl]-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(1.9 g, 4.66 mmol) and AgOTf (11.97 g, 46.59 mmol) in solvents DMF (15mL) and methanol (15 mL) was stirred at 90° C. for 96 hours. Aftercooling to room temperature, the reaction mixture was treated with brine(50 mL), and the precipitate was filtrated. The filtrate wasconcentrated and diluted with water (40 mL), then extracted with EtOAc(50 mL×2). The combined organic phase was washed with brine (50 mL),dried over Na₂SO₄ and concentrated to give a crude product. The crudeproduct was purified with flash chromatography on silica gel (EtOAc inPE=0% to 40%) to give the product (170 mg). Another 88 mg of the productwas obtained from other batch. Three batches of the product werecombined and lyophilized to give the product (193.0 mg, 0.48 mmol) as asolid. ¹H NMR (400 MHz, CDCl₃) δ=9.52 (d, 1H), 8.72 (d, 1H), 8.43 (s,1H), 8.19 (dd, 1H), 6.94 (d, 1H), 3.98 (s, 3H), 1.87 ppm (s, 6H). LCMSR_(t)=1.235 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. forC₁₆H₁₅F₅N₅O₂ [M+H]⁺ 404.1, found 403.9.

Example 54:3-[chloro(difluoro)methyl]-6-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A54: To a solution of 1-(trifluoromethyl)cyclobutanol (5 g,35.69 mmol) in THF (300 mL) was added NaH (1.86 g, 46.4 mmol) at 0° C.over 20 minutes, and the mixture was stirred at 0° C. for 30 mins. Thento the mixture was added 5-bromo-2-fluoro-pyridine (8.48 g, 48.18 mmol),and the mixture was stirred at 30° C. for 3 hours. The mixture wasquenched with sat. NH₄Cl (50 mL), then the mixture was extracted withEtOAc (50 mL). The combined organic phase was washed with brine (50mL×3), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct (4.8 g, 15.49 mmol, 43% yield) as an oil. LCMS R_(t)=0.99 min in1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₀H₁₀BrF₃NO [M+H]⁺295.9, found 296.0.

Synthesis of A55: A mixture of5-bromo-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (2.5 g, 8.44 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(3.22 g, 12.67 mmol), KOAc (1.66 g, 16.89 mmol) and Pd(dppf)Cl₂ (432.48mg, 0.59 mmol) in 1,4-Dioxane (50 mL) was stirred at 90° C. for 12 hoursunder N₂. After cooling to room temperature, the mixture wasconcentrated to give the residue. The residue was diluted with H₂O (40mL), and the mixture was extracted with EtOAc (40 mL×2). The combinedorganic phase was washed with water (40 mL) and brine (40 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 1%) to give the crude product (2.65 g, 3.92 mmol, 46% yield)as an oil. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.54 (d, 1H), 7.95 (dd, 1H),6.74 (d, 1H), 2.99-2.81 (m, 2H), 2.75-2.53 (m, 2H), 2.13-1.78 (m, 2H),1.34 (s, 12H).

Synthesis of A56: A mixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine(2.1 g, 6.12 mmol), 2-bromo-5-chloro-pyrazine (1.18 g, 6.12 mmol),Pd(dppf)Cl₂ (671.68 mg, 0.92 mmol) and Cs₂CO₃ (3.99 g, 12.24 mmol) in1,4-Dioxane (20 mL) and Water (2 mL) was stirred at 60° C. for 6 hoursunder N₂. After cooling to room temperature, the mixture wasconcentrated to give the residue. The residue was diluted with H₂O (20mL), and the mixture was extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with water (20 mL) and brine (40 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 1% to 10%) to give the product (1.5 g, 4.263 mmol, 70%yield) as an oil. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.80-8.72 (m, 2H), 8.63(d, 1H), 8.25 (dd, 1H), 6.91 (d, 1H), 3.01-2.83 (m, 2H), 2.78-2.62 (m,2H), 2.18-1.84 (m, 2H).

Synthesis of A57: A mixture of2-chloro-5-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazine (1.2g, 3.64 mmol) and hydrazine (1.17 g, 36.4 mmol) in MeCN (20 mL) washeated to 90° C. and stirred for 16 hours. After cooling to roomtemperature, the reaction mixture was concentrated and diluted with H₂O(30 mL) and extracted with EtOAc (30 mL×2). The combined organic phasewas washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated to give crude product (950 mg, 2.48 mmol, 68% yield) as asolid. LCMS R_(t)=0.99 min in 2.0 min chromatography, 10-80AB, MS ESIcalcd. for C₁₄H₁₅F₃N₅O [M+H]⁺ 326.1, found 326.0.

Synthesis of A58: A mixture of[5-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazin-2-yl]hydrazine(1.13 g, 3.47 mmol), 4A Molecular sieve (1 g, 3.47 mmol) and(2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (1.69 g,6.95 mmol) in Toluene (15 mL) was heated to 130° C. and stirred for 16hours. After cooling to room temperature, the reaction mixture wasfiltered and diluted with H₂O (50 mL) and extracted with EtOAc (50mL×2). The combined organic phase was washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product (820mg, 1.13 mmol, 33% yield) as a solid.

LCMS R_(t)=1.38 min in 2.0 min chromatography, 10-80AB, MS ESI calcd.for C₁₆H₁₂ClF₅N₅O [M+H]⁺ 420.1, found 420.0.

Synthesis of Compound 57: A mixture of3-[chloro(difluoro)methyl]-6-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(600 mg, 1.43 mmol), AgOTf (4.4 g, 17.15 mmol) in DMF (6 mL) andmethanol (6 mL, 1.43 mmol) was stirred at 90° C. for 16 hours. Aftercooling to room temperature, the reaction was quenched with sat. NaCl(30 mL) and extracted with EtOAc (30 mL×2). The organic layer was washedwith brine (30 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 40% to 70%) to give theproduct (194.76 mg, 0.47 mmol, 33% yield) as a solid. ¹H NMR (CDCl₃, 400MHz) δ_(H)=9.52 (d, 1H), 8.72 (d, 1H), 8.44 (d, 1H), 8.23 (dd, 1H),7.0-6.89 (m, 1H), 3.97 (s, 3H), 3.00-2.85 (m, 2H), 2.80-2.63 (m, 2H),2.13-1.89 (m, 2H). LCMS R_(t)=1.33 min in 2.0 min chromatography,10-80AB, MS ESI calcd. for C₁₇H₁₅F₅N₅O₂ [M+H]⁺ 416.1, found 416.1.

Example 56:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A59: A mixture of 2-bromo-5-chloro-3-methyl-pyrazine (900mg, 4.34 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(1.31 g, 3.9 mmol), Pd(dppf)Cl₂ (0.48 g, 0.65 mmol) and Cs₂CO₃ (2.83 g,8.68 mmol) in 1,4-Dioxane (40 mL) and Water (8 mL) was stirred under N₂at 50° C. for 5 hours. The mixture was cooled to room temperature,diluted with EtOAc (30 mL), filtered through silica gel and eluted withEtOAc (20 mL), and the filtrate was concentrated to give the crudeproduct. The product was purified by flash chromatography on silica gel(EtOAc in PE=0% to 3%) to give the product (1100 mg, 2.83 mmol, 65%yield) as a solid. LCMS R_(t)=1.41 min in 1.5 min chromatography,10-80AB, MS ESI calcd. for C₁₃H₁₁ClF₄N₃O [M+H]⁺ 336.0, found 336.0.

Synthesis of A60: A mixture of5-chloro-2-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-methyl-pyrazine(1.1 g, 3.28 mmol) and hydrazine (1.05 g, 32.83 mmol) in MeCN (20 mL)was heated to 90° C. and stirred for 16 hours. After cooling to roomtemperature, the reaction mixture was concentrated. The mixture wasdiluted with H₂O (20 mL), extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine (20 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product wastriturated from PE (5 mL) to give the product (800 mg, 2.41 mmol, 68%yield) as a solid. The crude product was used into the next step withoutfurther purification. LCMS R_(t)=0.75 min in 1.5 min chromatography,5-95AB, MS ESI calcd. for C₁₃H₁₄F₄N₅O [M+H]⁺ 332.1, found 332.1.

Synthesis of A61: To a mixture of[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-6-methyl-pyrazin-2-yl]hydrazine(500 mg, 1.51 mmol) in Toluene (10 mL) was added(2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (366.68 mg,1.51 mmol) and 4A Molecular Sieves (1 g). The reaction mixture wasstirred at 110° C. for 5 days. After cooling to room temperature, thereaction mixture was concentrated. The residue was diluted with sat.NaHCO₃ (30 mL), and the mixture was extracted with EtOAc (30 mL×2). Thecombined organic phase was washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give a residue. The residue waspurification by flash column on silica gel (EtOAc in PE=0% to 20%) togive the product (105 mg, 0.16 mmol, 11% yield) as a solid. LCMSR_(t)=0.92 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. forC₁₅H₁₁ClF₆N₅O [M+H]⁺ 426.0, found 426.2.

Synthesis of Compound 58: A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine(105 mg, 0.25 mmol) and AgOTf (633.7 mg, 2.47 mmol) in mixed solventMethanol (1 mL) and DMF (1 mL) was stirred at 90° C. for 48 hours. Aftercooling to room temperature, the reaction mixture was treated with brine(15 mL), and the precipitate was filtered off. The filtrate wasextracted with EtOAc (15 mL×2). The combined organic phase was driedover Na₂SO₄ and concentrated to give a crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to30% to 50%). The e product was then triturated from DCM (0.5 mL) andn-hexane (0.5 mL) to give the product (2.05 mg, 4.90 μmol, 2% yield). ¹HNMR (CDCl₃, 400 MHz) δ_(H)=9.39 (s, 1H), 8.11 (d, 1H), 7.69 (dd, 1H),5.94-5.86 (m, 1H), 3.92 (s, 3H), 2.88 (s, 3H), 1.60 (d, 3H). LCMSR_(t)=1.24 min in 2 min chromatography, 10-80AB, MS ESI calcd. forC₁₆H₁₄F₆N₅O₂ [M+H]⁺ 422.1, found 422.0.

Example 57:3-[difluoro(methoxy)methyl]-6-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A62: To a mixture of (25)-2-(trifluoromethyl)oxirane (3 g,26.77 mmol) in THF (25 mL) was added LiAlH₄ (0.5 g, 13.2 mmol) at 0° C.under N₂ over 30 minutes, then the mixture was stirred at 20° C. for 2hours. After cooling to 0° C., the mixture was quenched with water (0.9g), the mixture was stirred at 35° C. for 30 minutes. The mixture wasfiltered through Celite, eluted with THF (20 mL×2), the organic phasewas washed with brine (20 mL×2) and dried over Na₂SO₄, filtered to givethe crude product of (2S)-1,1,1-trifluoropropan-2-ol (3 g, 26.3 mmol,98% yield) as a solution in THF, which was used directly without anyfurther purification.

Synthesis of A63: To a solution of (2S)-1,1,1-trifluoropropan-2-ol inTHF (50 mL) was added NaH (0.8 g, 19.94 mmol) at 0° C. over 20 minutes,and the mixture was stirred at 0° C. for 40 minutes. Then to the mixturewas added 5-bromo-2-fluoro-pyridine (2.7 g, 15.34 mmol), and the mixturewas stirred at 50° C. for 2 hours. The mixture was quenched with sat.NH₄Cl (40 mL), extracted with EtOAc (60 mL), the combined organic phasewas washed with brine (40 mL×2), dried over Na₂SO₄, filtered andconcentrated to give the crude product (3.48 g, 9.29 mmol, 61% yield) asan oil. LCMS R_(t)=0.95 min in 1.5 min chromatography, 5-95AB, MS ESIcalcd. for C₈H₈BrF₃NO [M+H]⁺ 270.0, found 269.9.

Synthesis of A64: A mixture of5-bromo-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (3.48 g, 12.89mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(4.91 g, 19.33 mmol), KOAc (2.53 g, 25.77 mmol) and Pd(dppf)Cl₂ (1.13 g,1.55 mmol) in 1,4-Dioxane (35 mL) was stirred at 85° C. for 12 hoursunder N₂. After cooling to room temperature, the mixture wasconcentrated to give a residue. The residue was diluted with H₂O (30mL), and the mixture was extracted with EtOAc (40 mL×2). The combinedorganic phase was washed with water (40 mL) and brine (40 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 1%) to give the product (3 g, 5.72 mmol, 44% yield) as anoil. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.42 (d, 1H), 7.96 (dd, 1H), 6.93(d, 1H), 6.00-5.93 (m, 1H), 1.45 (d, 3H), 1.30 (s, 12H). LCMS R_(t)=1.02min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₄H₂₀BF₃NO₃[M+H]⁺ 318.1, found 318.1.

Synthesis of A65: A mixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(600 mg, 1.89 mmol), 2-bromo-5-chloro-pyrazine (329.39 mg, 1.7 mmol),Pd(dppf)Cl₂ (207.67 mg, 0.28 mmol) and Cs₂CO₃ (1232.88 mg, 3.78 mmol) in1,4-Dioxane (15 mL) and Water (1.5 mL) was stirred at 60° C. for 5 hoursunder N₂. After cooling to room temperature, the mixture wasconcentrated to give the residue. The residue was diluted with H₂O (20mL), and the mixture was extracted with EtOAc (30 mL×2). The combinedorganic phase was washed with water (20 mL) and brine (20 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 3%) to give the product (350 mg, 1.15 mmol, 61% yield) as anoil. LCMS R_(t)=0.95 min in 1.5 min chromatography, 5-95AB, MS ESIcalcd. for C₁₂H₁₀ClF₃N₃O [M+H]⁺ 304.0, found 304.1.

Synthesis of A66: A mixture of2-chloro-5-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazine(351.14 mg, 1.16 mmol) and hydrazine (741.21 mg, 23.13 mmol) in CH₃CN (5mL) was stirred at 90° C. for 16 hours. After cooling to roomtemperature, the reaction was quenched with sat.NH₄Cl (30 mL), and themixture was extracted with EtOAc (20 mL×2). The combined organic phasewas washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product (350 mg, 1.05 mmol, 91% yield) asa solid. LCMS R_(t)=0.74 min in 1.5 min chromatography, 5-95AB, MS ESIcalcd. for C₁₂H₁₃F₃N₅O [M+H]⁺ 300.1, found 300.1.

Synthesis of A67: A mixture of[5-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]hydrazine(350 mg, 1.17 mmol), (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (852.42 mg, 3.51 mmol) and 4A MolecularSieves (500 mg, 1.17 mmol) in Toluene (8 mL) was stirred at 120° C. for2 days. After cooling to room temperature, the reaction was quenchedwith saturated NaHCO₃ (20 mL), and the mixture was extracted with EtOAc(20 mL×2). The combined organic phase was washed with water (20 mL) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to give theproduct (420 mg, 1.01 mmol, 86% yield) as a solid. LCMS R_(t)=0.92 minin 1.5 min chromatography, 5-95ABMS ESI calcd. for C₁₄H₁₀ClF₅N₅O [M+H]⁺394.0, found 394.1.

Synthesis of Compound 59: A mixture of3-[chloro(difluoro)methyl]-6-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(420 mg, 1.07 mmol), AgOTf (3289.25 mg, 12.8 mmol) in DMF (6 mL) andmethanol (6 mL, 1.07 mmol) was stirred at 90° C. for 24 hours. Aftercooling to room temperature, the reaction was diluted with EtOAc (30 mL)and quenched with saturated NaCl (30 mL), and the mixture was filteredthrough Celite and eluted with EtOAc (10 mL). The filtrate was washedwith water (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 15% to 30%) togive the impure product. The impure product was triturated fromn-hexane/DCM (2:1, 6 mL) to give the product (118.39 mg, 0.30 mmol, 29%yield) as a solid. ¹H NMR (CD₃CN, 400 MHz) δ_(H)=9.46 (d, 1H), 8.81 (d,1H), 8.66 (d, 1H), 8.35 (dd, 1H), 6.99 (d, 1H), 5.99-5.88 (m, 1H), 3.94(s, 3H), 1.53 (d, 3H). LCMS R_(t)=1.28 min in 2.0 min chromatography,10-80AB, MS ESI calcd. for C₁₅H₁₃F₅N₅O₂ [M+H]⁺ 390.1, found 390.0.

Example 58:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A68: A mixture of 2-bromo-5-chloro-3-methyl-pyrazine (900mg, 4.34 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(1.31 g, 3.9 mmol), Pd(dppf)Cl₂ (0.48 g, 0.65 mmol) and Cs₂CO₃ (2.83 g,8.68 mmol) in 1,4-Dioxane (40 mL) and water (8 mL) was stirred under N₂at 55° C. for 16 hours. The mixture was cooling to room temperature,diluted with EtOAc (50 mL), filtered with silica gel, eluted with EtOAc(20 mL) and concentrated to give the crude product. The product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 20%)yielding the product (930 mg, 2.62 mmol, 60% yield) as a colorless oil.LCMS R_(t)=0.95 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. forC₁₃H₁₁ClF₄N₃O [M+H]⁺ 336.0, found 336.1.

Synthesis of A69: A mixture of hydrazine (1775.89 mg, 55.41 mmol) and5-chloro-2-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-methyl-pyrazine(930 mg, 2.77 mmol) in CH₃CN (10 mL) was stirred at 90° C. for 16 hours.After cooling to room temperature, the reaction was quenched withsat.NH₄Cl (30 mL), and the mixture was extracted with EtOAc (40 mL×2).The combined organic phase was washed with water (30 mL) and brine (30mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct (980 mg, 2.45 mmol, 89% yield) as a solid. LCMS R_(t)=0.75 minin 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₃H₁₄F₄N₅O [M+H]⁺332.1, found 332.2.

Synthesis of A70: A mixture of[5-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-6-methyl-pyrazin-2-yl]hydrazine(600 mg, 1.81 mmol), (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (1320.05 mg, 5.43 mmol) and 4A MolecularSieves (600 mg, 1.81 mmol) in Toluene (10 mL) was stirred at 120° C. for5 days. After cooling to room temperature, the reaction was quenchedwith saturated NaHCO₃ (20 mL), and the mixture was extracted with EtOAc(20 mL×2). The combined organic phase was washed with water (20 mL) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 40%) to give the product (140 mg, 0.22mmol, 12% yield) as a solid. LCMS R_(t)=0.92 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for C₁₅H₁₁ClF₆N₅O [M+H]⁺ 426.0,found 426.1.

Synthesis of Compound 60: A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine(140 mg, 0.33 mmol), AgOTf (1267.44 mg, 4.93 mmol) in DMF (2 mL) andmethanol (2 mL, 0.33 mmol) was stirred at 90° C. for 2 days. Aftercooling to room temperature, the reaction was diluted with EtOAc (10 mL)and saturated NaCl (10 mL), and the mixture was filtered through Celiteand eluted with EtOAc (10 mL). The combined organic phase was washedwith water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby Prep-TLC (silica gel, PE:EtOAc=2:1) to give the impure product. Theimpure product was triturated from n-hexane/DCM (2:1, 3 mL) to give theproduct (11.92 mg, 28.3 μmol, 9% yield) as a solid. ¹H NMR (CDCl₃, 400MHz) δ_(H)=9.39 (s, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 5.96-5.85 (m, 1H),3.92 (s, 3H), 2.88 (s, 3H), 1.60 (d, 3H). LCMS R_(t)=1.28 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₆H₁₄F₆N₅O₂ [M+H]⁺ 422.1,found 422.2.

Example 59:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A71: To a solution of 5-chloropyrazin-2-amine (25 g, 192.98mmol) in DCM (250 mL) was added NBS (34.35 g, 192.98 mmol). Theresulting mixture was stirred at 40° C. for 1 hour. After cooling toroom temperature and concentrated, water (200 mL) was added to giveresidue, extracted with EtOAc (150 mL×2). The combined organic phase waswashed with brine (150 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified bychromatography column on silica gel (EtOAc in PE=0% to 15% to 30%) togive the product (31 g, 148.72 mmol, 77% yield) as a solid. ¹H NMR(DMSO-d₆, 400 MHz) δ_(H)=8.09 (s, 1H), 6.96 (s, 2H).

Synthesis of A72: A mixture of 3-bromo-5-chloro-pyrazin-2-amine (31 g,148.72 mmol), Pd(dppf)Cl₂ (16.32 g, 22.31 mmol), methylboronic acid(13.35 g, 223.09 mmol) and Cs₂CO₃ (96.91 g, 297.45 mmol) in Water (30mL) and 1,4-Dioxane (300 mL) was stirred at 90° C. for 16 hours. Aftercooling to room temperature, the mixture was concentrated to give aresidue. To the residue was added water (100 mL), extracted with EtOAc(100 mL×2). The combined organic phase was washed with brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=20% to 40% to 60% to 80%) to give the product(13 g, 90.548 mmol, 61% yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz)δ_(H)=7.83 (s, 1H), 6.40 (s, 2H), 2.26 (s, 3H).

Synthesis of A73: A mixture of 5-chloro-3-methyl-pyrazin-2-amine (3 g,20.9 mmol), isopentyl nitrite (3.67 g, 31.34 mmol) and CuBr (3 g, 20.9mmol) in MeCN (30 mL) was stirred at 50° C. for 12 hours. The mixturewas diluted with H₂O (30 mL), and the mixture was extracted with EtOAc(70 mL×2). The combined organic phase was washed with water (30 mL×2)and brine (30 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flash columnchromatography on silica gel (DCM in PE=0% to 2%) to give the product(1.2 g, 5.78 mmol, 28% yield) as an oil. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=8.22 (s, 1H), 2.68 (s, 3H). LCMS R_(t)=1.10 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₅H₅BrClN₂ [M+H]⁺ 208.9,found 208.7.

Synthesis of A74: A mixture of 2-bromo-5-chloro-3-methyl-pyrazine (1.2g, 5.78 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(1.3 g, 4.05 mmol), Cs₂CO₃ (3.77 g, 11.57 mmol) and Pd(dppf)Cl₂ (634.85mg, 0.87 mmol) in 1,4-Dioxane (30 mL) and water (3 mL) was stirred at60° C. under N₂ for 16 hours. After cooling to room temperature, water(30 mL) and EtOAc (50 mL) were added to the mixture and the mixture wasfiltered through Celite. After the filtrate was separated, the organicphase was washed with brine (30 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash column chromatography on silica gel (EtOAc inPE=0% to 1% to 2%) to give the product (580 mg, 1.71 mmol, 30% yield) asa solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.52 (s, 1H), 8.19 (d, 1H), 7.73(dd, 1H), 4.91 (q, 2H), 2.69 (s, 3H). LCMS R_(t)=0.93 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for C₁₂H₉ClF₄N₃O [M+H]⁺ 322.0,found 322.0.

Synthesis of A75: A solution of5-chloro-2-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-methyl-pyrazine(640 mg, 1.89 mmol) and hydrazine (605.42 mg, 18.89 mmol) in MeCN (20mL) was stirred at 90° C. for 16 hours. After cooling to roomtemperature, the mixture was concentrated, water (20 mL) was added, andthe mixture was extracted with EtOAc (20 mL×3). The combined organicphase was washed with brine (20 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product (530 mg, 1.30 mmol,69% yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=8.18 (d, 1H),8.08 (s, 1H), 8.06 (s, 1H), 7.97 (dd, 1H), 5.13 (q, 2H), 4.32 (br s,2H), 2.41 (s, 3H). LCMS R_(t)=0.72 min in 1.5 min chromatography,5-95AB, MS ESI calcd. for C₁₂H₁₂F₄N₅O [M+H]⁺ 318.1, found 318.1.

Synthesis of A76: A solution of[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-6-methyl-pyrazin-2-yl]hydrazine(530 mg, 1.67 mmol), (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (1.22 g, 5.01 mmol) and 4A MolecularSieves (3 g) in Toluene (30 mL) was stirred at 120° C. for 6 days. Aftercooling to room temperature, the mixture was concentrated to give aresidue. To the residue was added water (50 mL) then extracted withEtOAc (50 mL×2). The combined organic phase was washed with water (50mL) and brine (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography column on silica gel (EtOAc in PE=0% to 15% to30%) to give the product (180 mg, 426.2 μmol, 26% yield) as an oil. LCMSR_(t)=3.64 min in 7.0 min chromatography, 10-80AB, MS ESI calcd. forC₁₄H₉ClF₆N₅O [M+H]⁺ 412.0, found 412.1.

Synthesis of Compound 61: A solution of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine(180 mg, 0.44 mmol) and AgOTf (1.69 g, 6.56 mmol) in Methanol (5 mL) andDMF (5 mL) was stirred at 90° C. under N₂ for 16 hours. After cooling toroom temperature, saturated NaCl (50 mL) and EtOAc (50 mL) were added tothe mixture and the mixture was filtered through Celite. Afterseparation, the organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by flash column chromatography on silicagel (EtOAc in PE=0% to 15% to 30%) to give the product (38.62 mg, 94.1μmol, 22% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=9.39 (s, 1H),8.12 (d, 1H), 7.71 (dd, 1H), 4.93 (q, 2H), 3.92 (s, 3H), 2.88 (s, 3H).LCMS R_(t)=1.20 min in 2.0 min chromatography, 10-80AB, MS ESI calcd.for C₁₅H₁₂F₆N₅O₂ [M+H]⁺ 408.1, found 407.9.

Example 60:3-[difluoro(methoxy)methyl]-6-[6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a suspension of3-[bromo(difluoro)methyl]-6-[6-[rac-(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(2.9 g, 6.62 mmol) in methanol (30 mL) was added AgBF₄ (2.58 g, 13.24mmol) at 25° C. under N₂. The mixture was protected from light andstirred at 60° C. for 1 hour. The solution was added to saturated NaCl(30 mL) and filtered. The filter was extracted with EtOAc (20 mL×2). Thecombined organic phase was washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated. The crude product was purified bychromatography flash column on silica gel (EtOAc in PE=0% to 10% to 20%)to give the product (1.96 g, ee=92.28%) as a solid. Analytical SFC:Analysis by SFC (Chiralpak OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A:CO₂, B: ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 5 min andfrom 40% to 5% of B in 0.5 min, hold 5% of B for 1.5 min; Flow rate: 2.5mL/min Column temp: 35° C.) showed two peaks at =2.71 min and 2.96 min.The product was separated by SFC (DAICEL CHIRALCEL OJ (250 mm×50 mm, 10∞cm); A=CO₂ and B=0.1% NH₃H₂O EtOH; 35° C.; 200 mL/min; 25% B; 8 minrun; 100 injections, Rt of peak 1=4.2 min and Peak 2=4.7 min) to givethe product (1415.6 mg, 3.64 mmol, 55% yield) as a solid. ¹H NMR (400MHz, CD₃CN) δ_(H)=9.45 (d, 1H), 8.80 (d, 1H), 8.66 (d, 1H), 8.35 (dd,1H), 6.99 (d, 1H), 5.97-5.90 (m, 1H), 3.94 (s, 3H), 1.53 (d, 3H). LCMSR_(t)=1.27 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. forC₁₅H₁₃F₅N₅O₂ [M+H]⁺ 389.1, found 390.0.

Example 61:3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of cyclopropanol (84.65 mg, 1.46 mmol),3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(300 mg, 0.73 mmol) in DMF (5 mL) was added potassium tert-butoxide(163.54 mg, 1.46 mmol). The reaction mixture was stirred at 20° C. for 1hour. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc(10 mL×2). The combined organic phase was washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=0% to 30%) to give the impure product. The impure productwas triturated from n-hexane/DCM (2:1, 3 mL) to give the product (33.18mg, 76.6 μmol, 11% yield). ¹H NMR (CDCl₃, 400 MHz) δ_(H)=9.52 (d, 1H),8.49 (d, 1H), 8.43 (d, 1H), 8.05 (dd, 1H), 5.96-5.86 (m, 1H), 4.21-4.16(m, 1H), 1.61 (d, 3H), 1.04-0.99 (m, 2H), 0.87-0.81 (m, 2H). LCMSR_(t)=1.34 min in 2.0 min chromatography, 10-80AB. MS ESI calcd. forC₁₇H₁₄F₆N₅O₂ [M+H]⁺ 434.1, found 434.1.

Example 62:6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A84: To a solution of phenylmethanol (10.5 g, 97.1 mmol) inTHF (100 mL) was added NaH (7 g, 175 mmol) in portions at 0° C. over 0.5hour. After the addition, the mixture was stirred at 20° C. for another1 hour. Then 5-bromo-2,3-difluoro-pyridine (18.83 g, 97.1 mmol) wasadded to the mixture. The resulting mixture was stirred at 20° C. for 3hours. The mixture was poured into saturated NH₄Cl solution (100 mL) andthe mixture was extracted with EtOAc (100 mL×2). The combined organicphase was washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product (27 g, 89.52 mmol)as an oil.

Synthesis of A85: A mixture of 2-benzyloxy-5-bromo-3-fluoro-pyridine (27g, 95.71 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(29.16 g, 114.85 mmol), KOAc (18.79 g, 191.41 mmol) and Pd(dppf)Cl₂(10.5 g, 14.36 mmol) in 1,4-dioxane (300 mL) was stirred at 90° C. underN₂ for 16 hours. After cooling to room temperature, the mixture wasfiltered through Celite and the filtrate was concentrated. The crudeproduct was purified by flash chromatography on silica gel (PE) to givethe product (20 g, 60.75 mmol, 63% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.30 (d, 1H), 7.66 (dd, 1H), 7.50 (d, 2H), 7.41-7.31 (m,3H), 5.52 (s, 2H), 1.35 (s, 12H).

Synthesis of A86: A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68mmol),2-benzyloxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(6.81 g, 20.68 mmol), Cs₂CO₃ (13.47 g, 41.36 mmol) and Pd(dppf)Cl₂ (2.27g, 3.1 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 50°C. under N₂ for 16 hours. After cooling to room temperature, the mixturewas filtered, and the filtrate was concentrated. Water (50 mL) was addedand the aqueous layer was extracted with EtOAc (50 mL×2). The combinedorganic layer was washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The crude product was purified byflash chromatography on silica gel (EtOAc in PE=0% to 15% to 30%) togive the product (5.5 g, 17.42 mmol, 84% yield) as a solid. ¹H NMR (400MHz, DMSO-d₆) δ_(H)=9.15 (s, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.37 (d,1H), 7.52-7.46 (m, 2H), 7.44-7.32 (m, 3H), 5.51 (s, 2H).

Synthesis of A87: A mixture of2-(6-benzyloxy-5-fluoro-3-pyridyl)-5-chloro-pyrazine (4.2 g, 13.3 mmol)and hydrazine (4.26 g, 133.03 mmol) in MeCN (20 mL) was stirred at 90°C. for 16 hours. After cooling to room temperature, the solution wasconcentrated under reduced pressure. Water (30 mL) was added and theaqueous layer was extracted with EtOAc (30 mL×2). The combined organicphase was washed with brine (30 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product (4 g, 7.38 mmol) asa solid. LCMS R_(t)=0.76 min in 1.5 min chromatography, 5-95AB, MS ESIcalcd. for C₁₆H₁₅FN₅O [M+H]⁺ 312.1, found 311.9.

Synthesis of A88: To the solution of 2-bromo-2,2-difluoro-acetylchloride (1.65 g, 8.53 mmol) in THF (30 mL) was added[5-(6-benzyloxy-5-fluoro-3-pyridyl)pyrazin-2-yl]hydrazine (2 g, 6.42mmol). The mixture was stirred at 20° C. for 1 hour. Water (30 mL) wasadded and the aqueous layer was extracted with EtOAc (30 mL×2). Thecombined organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give the crude product(900 mg, 1.92 mmol) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=11.40(s, 1H), 9.52 (s, 1H), 8.78 (d, 1H), 8.63 (d, 1H), 8.24 (dd, 1H), 8.14(d, 1H), 7.49 (d, 2H), 7.43-7.32 (m, 3H), 5.49 (s, 2H).

Synthesis of A89: To a mixture ofN′-[5-(6-benzyloxy-5-fluoro-3-pyridyl)pyrazin-2-yl]-2-bromo-2,2-difluoro-acetohydrazide(450 mg, 0.96 mmol) in DCM (9 mL) was added 2-methoxypyridine (230.74mg, 2.11 mmol) and Tf₂O (0.19 mL, 1.15 mmol). The mixture was stirred at20° C. for 16 hours. Water (50 mL) was added and the aqueous layer wasextracted with EtOAc (50 mL×2). The combined organic phase was washedwith saturated NaHCO₃ solution (30 mL) and brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to50%) to give the product (240 mg, 533.1 μmol, 55% yield) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H)=9.57 (d, 1H), 8.55 (d, 1H), 8.41 (s, 1H),8.01 (dd, 1H), 7.52 (d, 2H), 7.44-7.32 (m, 3H), 5.57 (s, 2H).

Synthesis of Compound 64: A mixture of6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine(240 mg, 0.53 mmol) and AgBF₄ (207.55 mg, 1.07 mmol) in ethanol (5 mL)was stirred at 60° C. in the dark for 1 hour. After cooling to roomtemperature, the mixture was filtered through Celite and the filtratewas concentrated. The crude product was purified by flash chromatographyon silica gel (EtOAc in PE=0% to 30% to 50%) to give the product (31.09mg, 74.8 μmol, 14% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=9.51(d, 1H), 8.50 (d, 1H), 8.46 (s, 1H), 8.00 (dd, 1H), 7.55-7.48 (m, 2H),7.44-7.33 (m, 3H), 5.56 (s, 2H), 4.37 (q, 2H), 1.51 (t, 3H). LCMSR_(t)=1.38 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. forC₂₀H₁₇F₃N₅O₂ [M+H]⁺ 416.1, found 416.0.

Example 63:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A100: A mixture of3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine(900 mg, 3.03 mmol) and AgBF₄ (1.17 g, 6.05 mmol) in methanol (10 mL)was stirred at 60° C. under dark for 1 hour. After cooling to roomtemperature, brine (50 mL) and EtOAc (50 mL) were added to the mixtureand the mixture was filtered through Celite. The organic phase wasseparated and washed with brine (30 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 30% to 50%) to give theproduct (180 mg, 724.0 μmol, 23% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=7.99 (s, 1H), 3.90 (s, 3H), 2.53 (s, 3H). LCMS R_(t)=0.78min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₈H₈ClF₂N₄O[M+H]⁺ 249.0, found 248.9.

Synthesis of Compound 65: A mixture of6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine(100 mg, 0.40 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(193.72 mg, 0.60 mmol), K₃PO₄ (170.78 mg, 0.80 mmol) and Pd(t-Bu₃P)₂(30.83 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) wasstirred at 80° C. under N₂ for 3 hours. After cooling to roomtemperature, water (20 mL) was added to the mixture and the aqueouslayer was extracted with EtOAc (20 mL×2). The combined organic phase waswashed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 30% to 50%) to give the product (64.84 mg,158.9 μmol, 39% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.20(d, 1H), 8.06 (s, 1H), 7.69 (dd, 1H), 4.94 (q, 2H), 3.88 (s, 3H), 2.48(s, 3H). LCMS R_(t)=1.18 min in 2.0 min chromatography, 10-80AB, MS ESIcalcd. for C₁₅H₁₂F₆N₅O₂ [M+H]⁺ 408.1, found 408.0.

Example 64:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(121.31 mg, 0.36 mmol),6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine(75 mg, 0.3 mmol), Pd(t-Bu₃P)₂ (23.13 mg, 0.05 mmol), K₃PO₄ (128.09 mg,0.6 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80° C.for 3 hours. After cooling to room temperature, the mixture wasconcentrated and diluted with H₂O (20 mL). The aqueous layer wasextracted with EtOAc (20 mL×2). The combined organic phase was washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified with flash chromatographyon silica gel (EtOAc 100%) to give the product (70.46 mg, 0.17 mmol, 55%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.18 (d, 1H), 8.06 (d,1H), 7.67 (dd, 1H), 5.97-5.86 (m, 1H), 3.88 (s, 3H), 2.49 (s, 3H), 1.61(d, 3H). LCMS Rt=1.24 min in 2 min chromatography, 10-80AB, MS ESIcalcd. C₁₆H₁₄F₆N₅O₂ [M+H]⁺ 422.1, found 422.0.

Example 65:3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of3-[bromo(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine(100 mg, 0.21 mmol) and AgBF₄ (82.81 mg, 0.43 mmol) in ethanol (1 mL)was stirred at 60° C. in the dark for 1 hour. After cooling to roomtemperature, EtOAc (30 mL) and saturated aqueous NaCl (30 mL) were addedto the mixture. The mixture was filtered through Celite and the phasesof the filtrate were separated. The aqueous phase was extracted withEtOAc (20 mL). The combined organic phase was washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 30% to 50%) to give impure product (55 mg) as a solid. Theimpure product was triturated from EtOH (1 mL) to give the product(19.57 mg, 21% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=9.39 (s,1H), 8.11 (d, 1H), 7.69 (dd, 1H), 5.96-5.85 (m, 1H), 4.32 (q, 2H), 2.90(s, 3H), 1.60 (d, 3H), 1.45 (t, 3H). LCMS R_(t)=1.34 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₆F₆N₅O₂ [M+H]⁺ 436.1,found 436.0.

Example 66:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A103: A mixture of 3,6-dichloro-4-methyl-pyridazine (14 g,85.89 mmol) and N₂H₄H₂O (4.29 g, 85.89 mmol) in ethanol (200 mL) wasstirred at 70° C. for 30 hours. After cooling to room temperature, thesuspension was filtered. The filter cake was washed with EtOH (50 mL×3)and dried in oven to give the product as a mixture of two regioisomers(A103, A103-2) and in a ratio of approximately 1:1 (determined by ¹HNMR) (8 g, 50.45 mmol, 58% yield) as a solid.

Synthesis of A99: A mixture of 6-chloro-5-methyl-pyridazin-3-amine (2.0g, 13.93 mmol), (6-chloro-4-methyl-pyridazin-3-yl)hydrazine and2-bromo-2,2-difluoro-acetyl chloride (5.4 g, 27.86 mmol) in toluene (80mL) was stirred at 120° C. for 16 hours. After cooling to roomtemperature, the mixture was concentrated, and the residue was dilutedwith H₂O (50 mL). The mixture was extracted with EtOAc (100 mL×2). Thecombined organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=20% to 40%to 60%) to give A99 (400 mg, 1.34 mmol, 10% yield) and A99-2 (600 mg,2.01 mmol, 14% yield) both as solids. A99 ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.08 (s, 1H), 2.58 (s, 3H). A99-2 ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.14 (s, 1H), 2.81 (s, 3H).

Synthesis of A100-a: A mixture of3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine(400 mg, 1.34 mmol) and AgBF₄ (523.5 mg, 2.69 mmol) in methanol (5 mL)was stirred at 55° C. in the dark for 12 hours. After cooling to roomtemperature, aqueous saturated NaCl solution (30 mL) and EtOAc (30 mL)were added.

The mixture was filtered through Celite and the filtrate was extractedwith EtOAc (30 mL). The combined organic phase was washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 30% to 50%) to give the product (230 mg, 0.93 mmol, 68% yield)as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.98 (d, 1H), 3.89 (s, 3H),2.53 (s, 3H). LCMS Rt=0.73 min in 1.5 min chromatography, 10-80AB, MSESI calcd. C₈H₈ClF₂N₄O [M+H]⁺ 249.0, found 248.8.

Synthesis of Compound 68: A mixture of6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine(70 mg, 0.28 mmol),3-fluoro-2-(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(113.22 mg, 0.34 mmol), K₃PO₄ (119.55 mg, 0.56 mmol) and Pd(t-Bu₃P)₂(21.58 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) wasstirred at 80° C. under N₂ for 3 hours. After cooling to roomtemperature, the mixture was filtered through Celite and the filtratewas concentrated. Water (20 mL) was added and the mixture was extractedwith EtOAc (20 mL×2). The combined organic phase was washed with brine(30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Thecrude product was purified by prep-TLC (silica gel, EtOAc) to give theproduct (65 mg, 154.3 μmol, 54% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.18 (d, 1H), 8.06 (d, 1H), 7.67 (dd, 1H), 5.96-5.87 (m,1H), 3.88 (s, 3H), 2.49 (s, 3H), 1.61 (d, 3H). LCMS R_(t)=1.31 min in2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₆H₁₄F₆N₅O₂ [M+H]⁺422.1, found 422.2.

Example 67:6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2,4]-triazolo[4,3-b]pyridazine

A mixture of6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (80mg, 0.38 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(197.03 mg, 0.56 mmol), K₃PO₄ (159.74 mg, 0.75 mmol) and Pd(t-Bu₃P)₂(28.84 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) was stirredat 80° C. under N₂ for 3 hours. After cooling to 25° C., the mixture wasfiltered through Celite and the filtrate was concentrated. Water (20 mL)was added and the mixture was extracted with EtOAc (20 mL×2). Thecombined organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The crude product waspurified by prep-HPLC (Waters XBridge BEH C18 (150 mm×25 mm, 5 μm) A=H₂O(0.075% NH₄HCO₃) and B=CH₃CN; 50-60% B over 9.5 min) to give the product(21.64 mg, 0.05 mmol, 14% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.15 (d, 1H), 8.00 (d, 1H), 7.62 (dd, 1H), 5.04 (s, 2H), 3.48 (s,3H), 2.45 (s, 3H), 1.90 (s, 6H). LCMS R_(t)=1.28 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₈F₄N₅O₂ [M+H]⁺ 400.1,found 400.1.

Example 68:6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (70mg, 0.33 mmol),3-fluoro-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(132.38 mg, 0.40 mmol), K₃PO₄ (139.78 mg, 0.66 mmol) and Pd(t-Bu₃P)₂(25.24 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) wasstirred at 80° C. under N₂ for 3 hours. After cooling to 25° C., themixture was filtered through Celite and the filtrate was concentrated.Water (20 mL) was added and the aqueous layer was extracted with EtOAc(20 mL×2). The combined organic phase was washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=10% to 20%) to give the product (33.02 mg, 0.09 mmol, 26% yield) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.16 (d, 1H), 8.00 (d, 1H), 7.65(dd, 1H), 5.96-5.86 (m, 1H), 5.04 (s, 2H), 3.49 (s, 3H), 2.46 (s, 3H),1.61 (d, 3H). LCMS R_(t)=1.24 min in 2.0 min chromatography, 10-80AB, MSESI calcd. for C₁₆H₁₆F₄N₅O₂ [M+H]⁺ 386.1, found 385.9.

Example 69:6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A105: The corresponding pinacol ester was dissolved in MeCNand aqueous HCl was added. The mixture was stirred for 2 hours at roomtemperature and then concentrated to give A105, which was used crude.

Synthesis of Compound 71: A mixture of6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (70mg, 0.33 mmol), [5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]boronicacid (94.39 mg, 0.40 mmol), K₃PO₄ (139.78 mg, 0.66 mmol) and Pd(t-Bu₃P)₂(25.24 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) wasstirred at 80° C. under N₂ for 3 hours. After cooling to roomtemperature, the mixture was filtered through Celite and the filtratewas concentrated. Water (20 mL) was added and the aqueous layer wasextracted with EtOAc (20 mL×2). The combined organic phase was washedwith brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by prep-TLC (silica gel,EtOAc) to give the product (9.8 mg, 0.03 mmol, 8% yield) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H)=8.17 (d, 1H), 8.01 (s, 1H), 7.68 (dd, 1H),5.04 (s, 2H), 4.93 (q, 2H), 3.49 (s, 3H), 2.45 (s, 3H). LCMS R_(t)=1.19min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₅H₁₄F₄N₅O₂[M+H]⁺ 372.1, found 372.0.

Example 70:6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

Synthesis of A104: To a solution of a mixture of(6-chloro-5-methyl-pyridazin-3-yl)hydrazine and(6-chloro-4-methyl-pyridazin-3-yl)hydrazine) (2 g, 12.61 mol) in toluene(30 mL) was added 2-methoxyacetyl chloride (2737.12 mg, 25.22 mmol) at25° C. The mixture was heated to 120° C. and stirred for 16 hours. Aftercooling to room temperature, the mixture was concentrated, and theresidue was diluted with H₂O (30 mL). The mixture was extracted withEtOAc (50 mL×2). The combined organic phase was washed with brine (10mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The crudeproduct was purified by flash chromatography on silica gel (EtOAc) for 3times to give the A104 (250 mg, 1.17 mmol, 9% yield) and A104-2 (500 mg,2.35 mmol, 19% yield) both as solids. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.94(d, 1H), 5.02 (s, 2H), 3.50 (s, 3H), 2.51 (s, 3H).

Synthesis of Compound 72: A mixture of6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (60mg, 0.28 mmol),3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(113.47 mg, 0.34 mmol), K₃PO₄ (119.81 mg, 0.56 mmol) and Pd(t-Bu₃P)₂(21.63 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) was stirredat 80° C. under N₂ for 1 hours. After cooling to room temperature, themixture was filtered through Celite and the filtrate was concentrated.Water (20 mL) was added and the mixture was extracted with EtOAc (20mL×2). The combined organic phase was washed with brine (30 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The crude product waspurified by prep-TLC (silica gel, EtOAc) to give the product (23.22 mg,59.2 μmol, 21% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.16 (d,1H), 8.01 (s, 1H), 7.65 (dd, 1H), 5.96-5.85 (m, 1H), 5.04 (s, 2H), 3.49(s, 3H), 2.45 (s, 3H), 1.61 (d, 3H). LCMS R_(t)=1.24 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₆H₁₆F₄N₅O₂ [M+H]⁺ 386.1,found 386.1.

Example 71:3-(difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A107: To a stirred solution of6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-c]pyrazine (1.0g, 4.18 mmol) and2-(3,3-difluorocyclobutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.43 g, 4.6 mmol) in 1,4-dioxane (27.0 mL) was added water (3.0 mL) andCs₂CO₃ (2.73 g, 8.37 mmol). Pd(dppf)Cl₂.DCM (0.34 g, 0.42 mmol) wasadded to the reaction mixture under nitrogen atmosphere and heated at80° C. for 16 hours. The reaction mixture was cooled to roomtemperature, filtered through Celite and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel with 25% ethyl acetate/PE to afford the product (430 mg, 1.11mmol, 26% yield). LCMS: 388.1 (M+H), Rt 2.4 min Column: ZORBAX XDB C-18(50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow Rate: 1.5 mL/min.

Synthesis of Compound 73: To a stirred solution of3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrazine(100 mg, 0.26 mmol) in MeCN (4.5 mL) was added Cs₂CO₃ (515 mg, 1.58mmol) and methanol (0.21 mL, 5.2 mmol). The reaction was stirred for 1 hat room temperature. The reaction mixture was treated with water (20.0mL) and extracted with ethyl acetate (2×20 mL). The organic layer waswashed with brine (15 mL), dried over anhydrous Na₂SO₄ and concentrated.The crude compound was purified by preparative HPLC to afford a solid(32 mg, 0.08 mmol, 32% yield). Prep-HPLC method: Rt=16.1; Column:XBridge C8 (150×19 mm), 5.0 μm; Mobile phase: 0.1% TFA inwater/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 4.49 min, Column:XBridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA in water, B:0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 384.1 (M+H), Rt 2.22 min,Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOHin water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz,CD₃OD): δ 9.54 (d, 1H), 8.86 (d, 1H), 8.78 (s, 1H), 8.39 (dd, 1H), 6.99(d, 1H), 5.25-5.22 (m, 1H), 3.99 (s, 3H), 3.23-3.13 (m, 2H), 2.82-2.70(m, 2H).

Example 72:3-(cyclopropoxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A109: To a stirred solution of 2,2,2-trifluoroethanol (3.12g, 31.25 mmol) in THF (25 mL) at 0° C. was added NaH (60% in mineraloil, 1.25 g, 31.25 mmol) in small portions. The reaction mixture wasslowly warmed to room temperature and stirred for 15 min.5-bromo-2-fluoro-pyridine (5.0 g, 28.41 mmol) was added drop-wise to thereaction mixture and stirred for 2 hours. The reaction mixture wascooled to 10° C. and treated with ice water (50 mL). The reactionmixture was extracted with ethyl acetate (2×60 mL). The organic layerwas washed with brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyon silica gel with 5% ethyl acetate/PE to afford the product (5.0 g,19.5 mmol, 68% yield) LCMS: 256.0 (M+H) and 258 (M+2+H), Rt 2.59 minColumn: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOHin water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of A110: To a stirred solution of5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (5.0 g, 19.53 mmol) andbis(pinacolato)diboron (6.45 g, 25.39 mmol) in 1,4-dioxane (50.0 mL) wasadded potassium acetate (3.83 g, 39.0 mmol). Pd(dppf)Cl₂.DCM (1.59 g,1.95 mmol) was added to the reaction mixture under nitrogen atmosphereand heated at 80° C. for 12 hours. The reaction mixture was cooled toroom temperature, filtered through Celite and concentrated under reducedpressure. The crude compound was purified by column chromatography onsilica gel with 5% ethyl acetate/PE to afford the product (4.32 g, 14.3mmol, 73% yield). LCMS: 304.1 (M+H), Rt 2.85 min Column: ZORBAX XDB C-18(50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow Rate: 1.5 mL/min.

Synthesis of A112: To a stirred solution of6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.3g, 5.44 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.5 g, 4.95 mmol) in 1,4-dioxane (25.0 mL) was added water(2.5 mL) and Cs₂CO₃ (3.22 g, 9.9 mmol). Pd(dppf)Cl₂.DCM (0.4 g, 0.49mmol) was added to the reaction mixture under nitrogen atmosphere andheated at 80° C. for 12 hours. The reaction mixture was cooled to roomtemperature, filtered through Celite and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel with 30% ethyl acetate/PE to afford the product (500 mg, 1.3mmol, 26% yield). LCMS: 380.0 (M+H), Rt 2.45 min Column: ZORBAX XDB C-18(50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow Rate: 1.5 mL/min.

Synthesis of Compound 74: To a stirred solution of3-(chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrazine(100 mg, 0.26 mmol) in MeCN (10 mL) was added Cs₂CO₃ (514 mg, 1.58 mmol)and cyclopropanol (0.21 mL, 3.29 mmol). The reaction was stirred for 1hour at room temperature. The reaction mixture was treated with water(15.0 mL) and extracted with ethyl acetate (2×20 mL). The organic layerwas washed with brine (15 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by preparative HPLC toafford a solid (10 mg, 0.024 mmol, 9% yield). Prep-HPLC method: Rt=14.2;Column: XBridge C8 (150×19 mm), 5.0 μm; Mobile phase: 0.1% TFA inwater/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.01 min, Column:XBridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA in water, B:0.1% TFA in ACN; Flow Rate: 2.0 mL/min LCMS: 402.1 (M+H), Rt 2.30 min,Column: XBridge C8 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% TFA inwater:ACN (95:5), B: 0.1% TFA in ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400MHz, CD₃OD): δ 9.55 (d, 1H), 8.89 (d, 1H), 8.75 (s, 1H), 8.43 (dd, 1H),7.09 (d, 1H), 4.98 (q, 2H), 4.26-4.23 (m, 1H), 0.99 (m, 2H), 0.85-0.81(m, 2H).

Example 73:3-(cyclopropoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A113: To a stirred solution of 2,2,2-trifluoroethanol (5.67g, 56.71 mmol) in THF (200 mL) at 0° C. was added NaH (60% in mineraloil, 2.26 g, 56.71 mmol) in small portions. The reaction mixture wasstirred for 15 min and 5-bromo-2,3-difluoro-pyridine (10.0 g, 51.55mmol) was added drop-wise. The reaction mixture was slowly warmed toroom temperature and stirred for 2 hours. The reaction mixture wascooled to 10° C. and treated with ice water (100 mL). The reactionmixture was extracted with ethyl acetate (2×100 mL). The organic layerwas washed with brine (80 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyon silica gel with 2% ethyl acetate/PE to afford the product (10.5 g,38.1 mmol, 73% yield). LCMS: 273.9 (M+H) and 276.0 (M+2+H), Rt 2.53 minColumn: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOHin water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of A3-a: To a stirred solution of5-bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine (3.0 g, 10.95 mmol)and bis(pinacolato)diboron (3.61 g, 14.23 mmol) in 1,4-dioxane (30.0 mL)was added potassium acetate (2.15 g, 21.9 mmol). Pd(dppf)Cl₂DCM (0.89 g,1.09 mmol) was added to the reaction mixture under nitrogen atmosphereand heated at 80° C. for 12 hours. The reaction mixture was cooled toroom temperature, filtered through Celite and concentrated under reducedpressure. The crude compound was purified by column chromatography onsilica gel with 15% ethyl acetate/PE to afford the product (2.0 g, 6.2mmol, 56% yield). LCMS: 322.1 (M+H), Rt 2.97 min Column: Atlantis dC18(50×4.6 mm), 5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow Rate: 1.5 mL/min.

Synthesis of A18-a: To a stirred solution of6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-c]pyrazine (2.0g, 8.37 mmol) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(2.96 g, 9.2 mmol) in 1,4-dioxane (26.0 mL) was added water (4.0 mL) andK₂CO₃ (2.31 g, 16.74 mmol). PdCl₂(PPh₃)₂ (0.59 g, 0.84 mmol) was addedto the reaction mixture under nitrogen atmosphere and heated at 90° C.for 12 hours. The reaction mixture was cooled to room temperature,filtered through Celite and concentrated under reduced pressure. Thecrude product was purified by column chromatography on silica gel with30% ethyl acetate/PE to afford the product (1.35 g, 3.4 mmol, 40%yield). LCMS: 398.0 (M+H), Rt 2.51 min Column: Atlantis dC-18 (50×4.6mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN;Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆): δ 9.77 (d, 1H), 9.14(s, 1H), 8.84 (d, 1H), 8.66 (dd, 1H), 5.20 (q, 2H).

Synthesis of Compound 75: To a stirred solution of3-(chlorodifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine(150.0 mg, 0.38 mmol) in MeCN (8.0 mL) was added Cs₂CO₃ (737 mg, 2.26mmol) and cyclopropanol (0.48 mL, 7.54 mmol). The reaction mixture wasstirred for 6 hours at room temperature. The reaction mixture wastreated with water (15.0 mL) and extracted with ethyl acetate (2×20 mL).The organic layer was washed with brine (15 mL), dried over anhydrousNa₂SO₄ and concentrated. The crude compound was purified by preparativeHPLC to afford a solid (15 mg, 0.035 mmol, 9% yield). Prep. HPLC method:Rt 14.8; Column) (Bridge C-18 (150×19 mm), 5.0 μm; Mobile phase: 0.1%TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.16 min,Column: XBridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA inwater, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 420.0 (M+H), Rt2.64 min, Column: Atlantis dC18 (50×4.6 mm), 3.5 μm Mobile Phase: A:0.1% HCOOH in water, B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz,DMSO-d₆): δ 9.71 (d, 1H), 8.93 (d, 1H), 8.78 (d, 1H), 8.56 (dd, 1H),5.19 (q, 2H), 4.24-4.20 (m, 1H), 0.96-0.92 (m, 2H), 0.77-0.72 (m, 2H).

Example 74:3-(difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A115: To stirred solution of 2-chloro-5-hydrazineylpyrazine(5.0 g, 33.99 mmol) in toluene (50 mL) was added chlorodifluoroaceticanhydride (6.54 mL, 37.39 mmol) at 0° C. The reaction mixture was heatedat 110° C. for 1 hour. The reaction mixture was cooled to roomtemperature and concentrated. The crude reaction mixture was treatedwith water (50 mL) and extracted with ethyl acetate (2×50 mL). Theorganic layer was washed with brine (30 mL), dried over Na₂SO₄ andconcentrated to a solid (6 g). It was used for the next step withoutfurther purification.

Synthesis of A111: To a stirred solution of2-chloro-N′-(5-chloropyrazin-2-yl)-2,2-difluoroacetohydrazide (6.0 mg,23.34 mmol) in DCM (120 mL) was added trifluoromethanesulfonic anhydride(4.73 mL, 28.01 mmol) and 2-methoxypridine (4.91 mL, 46.69 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature andstirred for 2 hours. The reaction mixture was treated with 10% sodiumbicarbonate solution (50 mL) and extracted with ethyl acetate (2×50 mL).The organic layer was washed with brine (50 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified by column chromatography onsilica gel with 15% EtOAc/PE to afford the product (4.0 g, 16.5 mmol,71% yield) as a solid. LCMS: 239.0 (M+H), Rt 1.66 min Column: ZORBAX XDBC-18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN(95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of A116: To a stirred solution of 3,3-difluorocyclobutanol(500 mg, 4.63 mmol) in THF (10 mL) at 0° C. was added NaH (60% inmineral oil, 204 mg, 5.09 mmol) in small portions. The reaction mixturewas slowly warmed to room temperature and stirred for 15 min.5-Bromo-2,3-difluoro-pyridine (0.9 g, 4.63 mmol) was then addeddrop-wise to the reaction mixture and stirred for 4 hours. The reactionmixture was cooled to 10° C. and treated with ice water (30 mL). Thereaction mixture was extracted with ethyl acetate (2×30 mL). The organiclayer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyon silica gel with 10% ethyl acetate/PE to afford the product (1.0 g,3.57 mmol, 77% yield). LCMS: 282.0 (M+H) and 284.0 (M+2+H), Rt 2.66 minColumn: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOHin water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of A117: To a stirred solution of5-bromo-2-(3,3-difluorocyclobutoxy)-3-fluoropyridine (1.1 g, 3.91 mmol)and bis(pinacolato)diboron (1.29 g, 5.09 mmol) in 1,4-dioxane (20.0 mL)was added potassium acetate (0.77 g, 7.83 mmol). Pd(dppf)Cl₂.DCM (0.32g, 0.39 mmol) was added to the reaction mixture under nitrogenatmosphere and heated at 90° C. for 16 hours. The reaction mixture wascooled to room temperature, filtered through Celite and concentratedunder reduced pressure. The crude compound was purified by columnchromatography on silica gel with 5% ethyl acetate/PE to afford theproduct (1.2 g, 3.6 mmol, 93% yield). LCMS: 330.1 (M+H), Rt 2.97 minColumn: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOHin water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of A118: To a stirred solution of6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-c]pyrazine (0.91g, 3.83 mmol) and2-(3,3-difluorocyclobutoxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.17 g, 3.55 mmol) in 1,4-dioxane (15.0 mL) was added water (3.0 mL)and Cs₂CO₃ (2.31 g, 7.13 mmol). Pd(dppf)Cl₂.DCM (0.29 g, 0.36 mmol) wasadded to the reaction mixture under nitrogen atmosphere and heated at80° C. for 8 hours. The reaction mixture was cooled to room temperature,filtered through Celite and concentrated under reduced pressure. Thecrude product was purified by column chromatography on silica gel with30% ethyl acetate/PE to afford the product (1.11 g, 2.75 mmol, 77%yield). LCMS: 405.9 (M+H), Rt 2.30 min Column: ZORBAX XDB C-18 (50×4.6mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN;Flow Rate: 1.5 mL/min.

Synthesis of Compound 76: To a stirred solution of3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine(140 mg, 0.34 mmol) in MeCN (7.5 mL) was added Cs₂CO₃ (668 mg, 2.06mmol) and methanol (0.14 mL, 3.4 mmol). The reaction was stirred for 1 hat room temperature. The reaction mixture was treated with water (20.0mL) and extracted with ethyl acetate (2×20 mL). The organic layer waswashed with brine (15 mL), dried over anhydrous Na₂SO₄ and concentrated.The crude compound was purified by preparative HPLC to afford a solid 08mg, 0.04 mmol, 13% yield.). Prep. HPLC method: Rt 12.9; Column: YMCPhenyl (150×19 mm), 5.0 μm; Mobile phase: 0.1% TFA inwater/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.01 min, 97.3%Column: XBridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA inwater, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 402.0 (M+H), Rt2.48 min, Column: Atlantis dC18 (50×4.6 mm), 5.0 μm Mobile Phase: A:0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR(400 MHz, DMSO-d₆): δ 9.70 (d, 1H), 8.97 (s, 1H), 8.77 (d, 1H), 8.49(dd, 1H), 5.30-5.26 (m, 1H), 3.92 (s, 3H), 3.26-3.19 (m, 2H), 2.89-2.84(m, 2H).

Example 75:6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-3-(ethoxydifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine(150 mg, 0.34 mmol)) in MeCN (7.5 mL) was added Cs₂CO₃ (668 mg, 2.06mmol) and ethanol (0.2 mL, 3.4 mmol). The reaction mixture was stirredfor 1 h at room temperature. The reaction mixture was treated with water(20.0 mL) and extracted with ethyl acetate (2×25 mL). The organic layerwas washed with brine (20 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by preparative HPLC toafford a solid (22 mg, 0.05 mmol, 15% yield). Prep. HPLC method: Rt13.1; Column: XBridge C-18 (150×19 mm), 5.0 μm; Mobile phase: 0.1% TFAin water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.08 min, 94.8%Column: XBridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA inwater, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 416.1 (M+H), Rt2.44 min, Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A:0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR(400 MHz, CD₃OD): δ 9.54 (d, 1H), 8.83 (d, 1H), 8.67 (d, 1H), 8.26 (dd,1H), 5.32-5.30 (m, 1H), 4.40 (q, 2H), 3.25-3.15 (m, 2H), 2.90-2.77 (m,2H), 1.49 (t, 3H).

Example 76:3-(cyclopropoxydifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine(100 mg, 0.26 mmol) in MeCN (9.0 mL) was added Cs₂CO₃ (504 mg, 1.55mmol) and cyclopropanol (0.33 mL, 5.16 mmol). The reaction mixture wasstirred for 4 h at room temperature. The reaction mixture was treatedwith water (20.0 mL) and extracted with ethyl acetate (2×20 mL). Theorganic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated. The crude compound was purified by preparative HPLC toafford a solid (14 mg, 0.034 mmol, 13% yield.). Prep. HPLC method: Rt10.67; Column: Sunfire C-18 (150×19 mm), 5.0 μm; Mobile phase: 0.1% TFAin water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.19 min,Column: XBridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA inwater, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 410.1 (M+H), Rt2.36 min, Column: XBridge C8 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1%TFA in water:ACN (95:5), B: 0.1% TFA in ACN; Flow Rate: 1.5 mL/min. ¹HNMR (400 MHz, CD₃OD): δ 9.54 (d, 1H), 8.84 (d, 1H), 8.71 (s, 1H), 8.37(dd, 1H), 7.00 (d, 1H), 5.25 (m, 1H), 4.26-4.23 (m, 1H), 3.23-3.13 (m,2H), 2.82-2.70 (m, 2H), 0.99 (m, 2H), 0.84-0.79 (m, 2H).

Example 77:3-(ethoxymethyl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A119: To a stirred solution of1,1,1-trifluoro-2-methylpropan-2-ol (0.57 g, 4.43 mmol) in THF (20 mL)at 0° C. was added NaH (60% in mineral oil, 0.23 g, 5.67 mmol) in smallportions. The reaction mixture was slowly warmed to room temperature andstirred for 15 min. 5-bromo-2,3-difluoro-pyridine (1.0 g, 5.16 mmol) wasadded drop-wise to the reaction mixture and stirred for 16 hours. Thereaction mixture was cooled to 10° C. and treated with ice water (30mL). The reaction mixture was extracted with ethyl acetate (2×50 mL).The organic layer was washed with brine (30 mL), dried over anhydrousNa₂SO₄ and concentrated. The crude compound was purified by columnchromatography on silica gel with 2% ethyl acetate/PE to afford theproduct (765 mg, 2.54 mmol, 49% yield). ⁺H NMR (400 MHz, CDCl₃): δ 7.99(d, 1H), 7.54 (dd, 1H), 1.80 (s, 6H).

Synthesis of A8: To a stirred solution of5-bromo-3-fluoro-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridine(765 mg, 2.54 mmol) and bis(pinacolato)diboron (0.71 g, 2.79 mmol) in1,4-dioxane (20.0 mL) was added potassium acetate (497 mg, 5.07 mmol).Pd(dppf)Cl₂.DCM (0.21 g, 0.25 mmol) was added to the reaction mixtureunder nitrogen atmosphere and heated at 80° C. for 16 hours. Thereaction mixture was cooled to room temperature, filtered through Celiteand concentrated under reduced pressure. The crude compound was purifiedby column chromatography on silica gel with 30% ethyl acetate/PE toafford the product_(300 mg, 0.86 mmol, 33% yield). LCMS: 350.1 (M+H), Rt3.31 min Column: Atlantis dC18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1%HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of A120: To a stirred solution of(5-chloropyrazin-2-yl)hydrazine (2.0 g, 13.53 mmol) in DCM (15 mL) wasadded Et₃N (3.78 mL, 27.07 mmol) followed by 2-ethoxyacetyl chloride(2.36 mL, 13.53 mmol) at 0° C. The reaction mixture was slowly warmed toroom temperature and stirred for 16 hours. The reaction mixture wastreated with saturated ammonium chloride solution (25 mL) and extractedwith ethyl acetate (2×25 mL). The organic layer was washed with brine(20 mL), dried over Na₂SO₄ and concentrated. The crude product waspurified by column chromatography on silica gel with 22% EtOAc/PE toafford the product (0.8 g, 3.47 mmol, 25% yield). LCMS: 231.1 (M+H), Rt1.07 min Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A:0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of A41-a: To a stirred solution ofN′-(5-chloropyrazin-2-yl)-2-ethoxyacetohydrazide (400 mg, 1.73 mmol) inDCM (15.0 mL) was added trifluoromethanesulfonic anhydride (0.38 mL,2.25 mmol) and 2-methoxypridine (377 mg, 3.46 mmol) at 0° C. Thereaction mixture was slowly warmed to room temperature and stirred for16 hours. The reaction mixture was treated with 10% sodium bicarbonatesolution (20 mL) and extracted with ethyl acetate (2×25 mL). The organiclayer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated.The crude product was purified by column chromatography on silica gelwith 35% EtOAc/PE to afford the product (100 mg, 0.47 mmol, 27% yield).LCMS: 213.1 (M+H), Rt 1.46 min Column: Atlantis dC18 (50×4.6 mm), 5.0 μmMobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5mL/min.

Synthesis of Compound 79: To a stirred solution of6-chloro-3-(ethoxymethyl)-[1,2,4]triazolo[4,3-c]pyrazine (150 mg, 0.71mmol) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridine(271 mg, 0.78 mmol) in 1,4-dioxane (10.0 mL) was added water (1.0 mL)and Cs₂CO₃ (460 mg, 1.41 mmol). Pd(dppf)Cl₂.DCM (57 mg, 0.07 mmol) wasadded to the reaction mixture under nitrogen atmosphere and heated at80° C. for 16 hours. The reaction mixture was cooled to roomtemperature, filtered through Celite and concentrated under reducedpressure. The crude compound was purified by preparative HPLC to afforda solid 1105 mg, 0.26 mmol, 36% yield). Prep. HPLC method: Rt 12.75;Column: X-Select (150×19 mm), 5.0 μm; Mobile phase: 0.1% TFA inwater/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 4.95 min, Column:XBridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA in water, B:0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 400.3 (M+H), Rt 2.41 min,Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOHin water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz,DMSO-d₆): δ 9.56 (d, 1H), 9.17 (d, 1H), 8.78 (d, 1H), 8.45 (dd, 1H),5.09 (s, 2H), 3.61 (q, 2H), 1.83 (s, 6H), 1.15 (t, 3H).

Example 79:3-(ethoxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of3-(chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine(190 mg, 0.50 mmol)) in MeCN (10.0 mL) was added Cs₂CO₃ (978 mg, 3.0mmol) and ethanol (0.58 mL, 10 mmol) at room temperature and stirred for3 hours. The reaction mixture was treated with water (15 mL) andextracted with ethyl acetate (2×20 mL). The organic layer was washedwith brine (15 mL), dried over anhydrous Na₂SO₄ and concentrated. Thecrude compound was purified by preparative HPLC to afford a solid (10mg, 0.025 mmol, 5.1% yield). Prep-HPLC method: Rt 9.35; Column: XBridge(150×19 mm), 5.0 μm; 0.1% TFA in water/acetonitrile; Flow Rate: 15.0mL/min. HPLC: Rt 4.89 min, Column: XBridge C8 (50×4.6) mm, 3.5 μm Mobilephase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min.LCMS: 390.0 (M+H), Rt 2.70 min, Column: Atlantis dC-18 (50×4.6 mm), 5 μmMobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5mL/min. ¹H NMR (400 MHz, CDCl₃): δ 9.54 (d, 1H), 8.74 (d, 1H), 8.48 (d,1H), 8.26 (dd, 1H), 7.06 (d, 1H), 4.87 (q, 2H), 4.38 (q, 2H), 1.52 (t,3H).

Example 80:3-(difluoro(isobutoxy)methyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 2-methylpropan-1-ol (4.65 mL, 50.29 mmol) inMeCN (20 mL) was added Cs₂CO₃ (4.92 g, 15.09 mmol) and reaction mixtureheated at 70° C. for 20 min. The reaction mixture was cooled to roomtemperature and3-(chlorodifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrazine(1.0 g, 2.51 mmol) was added. The reaction mixture was stirred for 4 hat room temperature and treated with water (30 mL). The reaction mixturewas extracted with ethyl acetate (2×30 mL), washed with brine (20 mL),dried over Na₂SO₄ and concentrated. The crude compound was purified bypreparative HPLC to afford a solid (35 mg, 0.08 mmol, 3% yield.).Prep-HPLC method: Rt 9.37; Column: XBridge C8 (150×19 mm), 5.0 μm; 0.1%TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.60 min,Column: XBridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA inwater, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 436.1 (M+H), Rt2.63 min, Column: XBridge C8 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1%TFA in water:ACN (95:5), B: 0.1% TFA in ACN; Flow Rate: 1.5 mL/min. ¹HNMR (400 MHz, DMSO-d₆): δ 9.72 (d, 1H), 8.97 (d, 1H), 8.77 (d, 1H), 8.54(dd, 1H), 5.19 (q, 2H), 4.04 (d, 2H), 2.10-2.02 (m, 1H), 0.98 (d, 6H).

Example 81:5-[3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]pyridin-2-oland6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A92: To a solution of phenylmethanol (12 g, 110.97 mmol) inTHF (100 mL) was added NaH (4.88 g, 122.06 mmol) in portions at 0° C.over 0.5 hour. After the addition, the mixture was stirred at 20° C. foranother 1 hour. Then 5-bromo-2-fluoro-pyridine (18.55 g, 105.4 2 mmol)was added to the mixture. The resulting mixture was stirred at 20° C.for 3 hours. The mixture was poured into saturated aqueous NH₄ (150 mL)and extracted with EtOAc (200 mL×2). The combined organic phase waswashed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product (27 g, 95.62 mmol, 86% yield) asan oil. LCMS R_(t)=0.96 min in 1.5 min chromatography, 5-95AB, MS ESIcalcd. for C₁₂H₁₁BrNO[M+H+2]⁺ 266.0, found 265.8.

Synthesis of A93: A mixture of 2-benzyloxy-5-bromo-pyridine (27 g,102.23 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(31.15 g, 122.67 mmol), KOAc (20.06 g, 204.45 mmol) and Pd(dppf)Cl₂(7.48 g, 10.22 mmol) in 1,4-dioxane (300 mL) was stirred at 90° C. underN₂ for 16 hours. After cooling to room temperature, the mixture wasfiltered through Celite and concentrated to give the crude product. Thecrude product was filtered through silica gel (50 g) and eluted withPE/EtOAc (5:1, 150 mL×5), and the filtrate was concentrated to give theimpure product. The impure product was triturated from i-Pr₂O (100 mL)to give the product (20 g, 64.27 mmol, 63% yield) as a solid.

LCMS R_(t)=0.74 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. forC₁₂H₁₃BNO₃[M−C₆H₁₀+H]⁺ 230.1, found 230.0.

Synthesis of A94: A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68mmol),2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(7.08 g, 22.75 mmol), Cs₂CO₃ (13.47 g, 41.36 mmol) and Pd(dppf)Cl₂ (1.51g, 2.07 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was stirred at50° C. under N₂ for 3 hours. After cooling to room temperature, themixture was filtered and concentrated to give a residue. To the residuewas added water (100 mL), extracted with EtOAc (150 mL×2). The combinedorganic phase was washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was filtered through silica gel (50 g) and eluted with DCM (150mL×3). The filtrate was concentrated to give the impure product. Theimpure product was triturated from i-Pr₂O (15 mL) to give the product of(4 g, 13.44 mmol, 65% yield) as a solid. LCMS R_(t)=1.03 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for C₁₆H₁₃ClN₃O [M+H]⁺ 298.1,found 297.9.

Synthesis of A95: A mixture of2-(6-benzyloxy-3-pyridyl)-5-chloro-pyrazine (4 g, 13.43 mmol) andN₂H₄.H₂O (8.61 g) in MeCN (20 mL) was stirred at 90° C. for 16 hours.After cooling to room temperature, the solution was concentrated to givea residue. To the residue was added water (30 mL), extracted with EtOAc(50 mL×3). The combined organic phase was washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give theproduct (4 g, 7.84 mmol, 58% yield) as a solid. LCMS R_(t)=0.74 min in1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₆H₁₆N₅O [M+H]⁺294.1, found 293.9.

Synthesis of A96: To a solution of 2-bromo-2,2-difluoro-acetyl chloride(1.78 g, 9.2 mmol) in DCM (20 mL) was added[5-(6-benzyloxy-3-pyridyl)pyrazin-2-yl]hydrazine (1.8 g, 6.14 mmol), andthe suspension was stirred at 20° C. for 2 hours. The mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (100 mL×2). Thecombined organic phase was washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=20% to 40%to 60% to 80%) to give the product of (1.5 g, 3.33 mmol, 54% yield) as asolid. LCMS R_(t)=0.88 min in 1.5 min chromatography, 10-80AB, MS ESIcalcd. for C₁₈H₁₅F₂N₅O₂ [M+H]⁺ 450.0, found 449.9.

Synthesis of A97: To a mixture ofN′-[5-(6-benzyloxy-3-pyridyl)pyrazin-2-yl]-2-bromo-2,2-difluoro-acetohydrazide(1.3 g, 2.89 mmol) in DCM (10 mL) was added 2-methoxypyridine (0.67 mL,6.35 mmol) and Tf₂O (0.59 mL, 3.46 mmol), and the mixture was stirred at20° C. for 2 hours. To the mixture was added water (20 mL), extractedwith DCM (50 mL×2). The combined organic phase was washed with saturatedaqueous NaHCO₃ (30 mL) and brine (30 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by chromatography flash column on silica gel (EtOAc in PE=0% to30% to 50%) to give the product (400 mg, 0.93 mmol, 32% yield) as asolid. LCMS R_(t)=0.93 min in 1.5 min chromatography, 10-80AB, MS ESIcalcd. for C₁₈H₁₃BrF₂N₅O [M+H+2]⁺ 434.0, found 434.0.

Synthesis of 83: A mixture of6-(6-benzyloxy-3-pyridyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine(400 mg, 0.93 mmol) and AgBF₄ (900.79 mg, 4.63 mmol) in methanol (4 mL)was stirred at 60° C. under dark for 2 hours. After cooling to roomtemperature, saturated aqueous NaCl (10 mL) was added to the mixturefollowed by EtOAc (30 mL), and the mixture was filtered through Celite.After the phases of the filtrate were separated, the organic phase waswashed with brine (30 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=20% to 40%) to give the impureproduct (150 mg), which was triturated from i-Pr₂O (2 mL) to give thepure product (130 mg). The product (39.76 mg, 0.10 mmol, 11% yield) wasobtained as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=9.52 (d, 1H), 8.76(d, 1H), 8.42 (d, 1H), 8.19 (dd, 1H), 7.53-7.47 (m, 2H), 7.45-7.32 (m,3H), 6.98 (d, 1H), 5.48 (s, 2H), 3.97 (s, 3H). LCMS R_(t)=1.26 min in2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₉H₁₆F₂N₅O₂ [M+H]⁺384.1, found 384.1.

Example 82:3-(difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine

To a suspension of Cs₂CO₃ (928 mg, 2.85 mmol) in CH₃CN (2.0 mL) wasadded methanol (0.23 mL, 5.7 mmol) at room temperature. The reactionmixture was stirred at room temperature for 10 min. and a solution of3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine(190 mg, 0.47 mmol) in CH₃CN (10.0 mL) was added dropwise. The reactionmixture was stirred for 2 hours at room temperature. The reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(2×25 mL). The organic layer was washed with brine (20 mL), dried overNa₂SO₄ and concentrated. The crude product was purified by preparativeHPLC to afford the product (50 mg, 0.12 mmol, 26% yield) as a solid.Prep. HPLC method: Rt 11.75; Column: X-Bridge (150×19 mm), 5.0 μm;Mobile phase: 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min.HPLC: Rt 4.64 min, 99.8% Column: X-Bridge C8 (50×4.6) mm, 3.5 μm Mobilephase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min.LCMS: 401.1 (M+H), Rt 2.22 min, 99.6% Column: ZORBAX XDB C-18 (50×4.6mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN;Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, CD₃OD): δ 8.65 (s, 1H), 8.31 (d,1H), 8.00-7.97 (m, 2H), 7.90 (dd, 1H), 5.32-5.28 (m, 1H), 3.96 (s, 3H),3.26-3.15 (m, 2H), 2.89-2.77 (m, 2H).

Example 83:6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-3-(ethoxydifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine

Synthesis A11: To a stirred solution of 5-bromo-2-fluoro-pyridine (10.0g, 56.82 mmol) in ethanol (120 mL) was added hydrazine hydrate (11.38 g,227 mmol) and heated to 80° C. for 12 hours The reaction mixture wascooled to room temperature and treated with ice water (200 mL). Theprecipitated solid was filtered, washed with water and dried to get theproduct (10.7 g) as a solid. It was used for the next step withoutfurther purification.

Synthesis of A127: To a stirred solution of A11 (2.0 g, 10.6 mmol) intoluene (25 mL) was added 2-chloro-2,2-difluoroacetic anhydride (2.84 g,11.7 mmol) at 0° C. The reaction mixture was heated at 100° C. for 1hour. The reaction mixture was cooled to room temperature andconcentrated. The crude reaction mixture was treated with water (50 mL)and extracted with ethyl acetate (2×50 mL). The organic layer was washedwith sat NaHCO₃ solution (20 mL) followed by brine (30 mL), dried overNa₂SO₄ and concentrated to afford the product (2.7 g) as a solid. It wasused for the next step without further purification.

Synthesis of A128: To a stirred solution of A127 (2.7 g, 8.99 mmol) inDCM (30 mL) was added trifluoromethanesulfonic anhydride (1.66 mL, 9.88mmol) and 2-methoxypridine (1.96 g, 17.97 mmol) at 0° C. The reactionmixture was slowly warmed to room temperature and stirred for 1 hour Thereaction mixture was treated with 10% sodium bicarbonate solution (50mL) and extracted with DCM (2×50 mL). The organic layer was washed withbrine (50 mL), dried over Na₂SO₄ and concentrated. The crude product waspurified by column chromatography on silica gel with 20% EtOAc/PE toafford the product (1.1 g, 3.9 mmol, 43% yield). LCMS: 282.0 (M+H) and284.0 (M+2+H), Rt 1.72 min Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm

Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5mL/min.

Synthesis of A125: To a stirred solution of A128 (1.0 g, 3.54 mmol) and2-(3,3-difluorocyclobutoxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.28 g, 3.89 mmol) in 1,4-dioxane (20.0 mL) was added water (4.0 mL)and K₂CO₃ (0.98 g, 7.08 mmol). Pd(PPh₃)₂Cl₂ (0.25 g, 0.35 mmol) wasadded to the reaction mixture under nitrogen atmosphere and heated at80° C. for 16 hours The reaction mixture was cooled to room temperatureand filtered through Celite. The crude reaction mixture was treated withwater (30 mL) and extracted with ethyl acetate (2×30 mL). The organiclayer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyon silica gel with 40% ethyl acetate/PE to afford the compound (1.1 g,2.7 mmol, 76% yield) as a solid. LCMS: 405.0 (M+H), Rt 2.68 min Column:Atlantis dC-18 (50×4.6 mm), 5.0 μm Mobile Phase: A: 0.1% HCOOH inwater:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of Compound 85: To a suspension of Cs₂CO₃ (966 mg, 2.97 mmol)in CH₃CN (2.0 mL) was added ethanol (0.35 mL, 5.93 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 10min. and a solution of A125 (200 mg, 0.49 mmol) in CH₃CN (10.0 mL) wasadded dropwise. The reaction mixture was stirred for 1 h and ethanol(0.35 mL, 5.93 mmol) was added at room temperature. The reaction mixturewas stirred for another 1 h at room temperature. The reaction mixturewas treated with water (20 mL) and extracted with ethyl acetate (2×25mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄and concentrated. The crude product was purified by columnchromatography on silica gel with 22% EtOAc/PE to afford the product (30mg, 0.07 mmol, 14% yield) as a solid. HPLC: Rt 4.92 min, 99.9% Column:X-Bridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA in water, B:0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 415.1 (M+H), Rt 2.53 min,99.8% Column: Atlantis dC-18 (50×4.6 mm), 5.0 μm. Mobile Phase: A: 0.1%HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400MHz, CD₃OD): δ 8.65 (s, 1H), 8.30 (d, 1H), 8.00-7.96 (m, 2H), 7.89 (dd,1H), 5.32-5.29 (m, 1H), 4.36 (q, 2H), 3.26-3.16 (m, 2H), 2.89-2.78 (m,2H), 1.47 (t, 3H).

Example 84:(R)-3-(ethoxydifluoromethyl)-6-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A77: To a solution of A132 (2.2 g, 19.63 mmol) in THF (20.0mL) was added LiAlH₄ (2.0 M in THF, 4.91 mL, 9.82 mmol) dropwise at 0°C. The reaction mixture was slowly warmed to room temperature andstirred for 3 hours. The reaction mixture was cooled to 0° C. andtreated with sat Na₂SO₄ solution (2.0 mL). The reaction mixture wasfiltered through Celite, the filtrate was dried over Na₂SO₄ and used forthe next step as a solution in THF.

Synthesis of A78: To a solution of A77 (30.68 mmol) in THF was added NaH(1.84 g, 46 mmol) portion wise at 0° C. and stirred for 30 min.5-bromo-2-fluoro-pyridine (4.32 g, 24.55 mmol) was added to the reactionmixture slowly at 0° C. The reaction mixture was slowly warmed to roomtemperature and stirred for 3 hours. The reaction mixture was cooled to10° C., treated with ice water (10 mL) and extracted with ethyl acetate(2×50 mL). The organic layer was washed with brine (40 mL), dried overNa₂SO₄ and concentrated. The crude product was purified by columnchromatography on silica gel with 20% EtOAc/PE to afford the product(3.1 g, 11.5 mmol, 37% yield) as a colourless liquid. LCMS: 270.0 (M+H)and 272.0 (M+2+H), Rt 2.78 min Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate:1.5 mL/min.

Synthesis of A79: To a stirred solution of A78 (3.1 g, 11.5 mmol) andbis(pinacolato)diboron (3.79 g, 14.92 mmol) in 1,4-dioxane (35.0 mL) wasadded potassium acetate (2.25 g, 22.96 mmol). Pd(dppf)Cl₂.DCM (1.41 g,1.72 mmol) was added to the reaction mixture under nitrogen atmosphereand heated at 90° C. for 12 hours. The reaction mixture was cooled toroom temperature, filtered through Celite and concentrated under reducedpressure. The crude compound was purified by column chromatography onsilica gel with 6% ethyl acetate/PE to afford the product (2.8 g, 8.83mmol, 76% yield) as a solid. LCMS: 318.0 (M+H), Rt 4.04 min Column:ZORBAX Extend (50×4.6 mm), 5 μm Mobile Phase: A: 10 mM Ammonium acetatein water, B: ACN; Flow Rate: 1.2 mL/min.

Synthesis of A82: To a stirred solution of A79 (0.5 g, 1.58 mmol) and6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (0.45g, 1.89 mmol) in 1,4-dioxane (12.0 mL) was added water (2.0 mL) andCs₂CO₃ (1.03 g, 3.15 mmol). Pd(dppf)Cl₂.DCM (0.11 g, 0.16 mmol) wasadded to the reaction mixture under nitrogen atmosphere and heated at90° C. for 16 hours. The reaction mixture was cooled to roomtemperature, filtered through Celite and concentrated under reducedpressure. The crude compound was purified by column chromatography onsilica gel with 15% ethyl acetate/PE to afford the product (350 mg, 0.89mmol, 56% yield) as a solid. LCMS: 394.1 (M+H), Rt 2.54 min Column:ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH inwater:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of Compound 86: To a stirred suspension of Cs₂CO₃ (993 mg,3.05 mmol) in MeCN (5.0 mL) was added ethanol (0.36 mL, 6.1 mmol) atroom temperature and stirred for 30 min. To the reaction mixture A82(200 mg, 0.51 mmol) in MeCN (5.0 mL) was added dropwise and stirred for2 hours. The reaction mixture was treated with water (30 mL) andextracted with ethyl acetate (2×30 mL). The organic layer was washedwith brine (20 mL), dried over Na₂SO₄ and concentrated The crudecompound was purified by column chromatography on silica gel with 18%ethyl acetate/PE to afford the product (35 mg, 0.08 mmol, 17% yield) asa solid. HPLC: Rt 5.22 min, 97.6% Column: X-Bridge C8 (50×4.6) mm, 3.5μm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate:2.0 mL/min. LCMS: 404.1 (M+H), Rt 2.53 min, 96.7% Column: ZORBAX ExtendC-18 (50×4.6 mm), 5.0 μm Mobile Phase: A: 10 mM Ammonium acetate inwater, B: ACN; Flow Rate: 1.2 mL/min. Chiral method: Rt 1.54 min, SFCcolumn: Chiralcel OJ-H; mobile phase: 60:40 (A: B), A=liquid CO₂, B=0.5%isopropyl amine in methanol; flow rate: 3.0 mL/min; wave length: 254 nm.¹H NMR (400 MHz, CD₃OD): δ 9.55 (d, 1H), 8.88-8.87 (m, 1H), 8.80 (d,1H), 8.42 (dd, 1H), 7.03 (dd, 1H), 6.00-5.93 (m, 1H), 4.39 (q, 2H),1.55-1.48 (m, 6H).

Example 84: 3-(methoxymethyl)-6-(64(1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A130: To a stirred solution of methoxyacetic acid (958 mg,10.64 mmol) in DMF (30.0 mL) was added Et₃N (2.97 mL, 21.27 mmol)followed by T3P (50% in ethyl acetate, 0.43 mL, 21.27 mmol) and5-bromo-2-hydrazineylpyridine (2.0 g, 10.64 mmol). The reaction mixturewas stirred at room temperature for 4 hours The reaction mixture wastreated with water (30 mL) and extracted with ethyl acetate (2×30 mL).The organic layer was washed with brine (40 mL), dried over anhydrousNa₂SO₄ and concentrated. The crude compound was purified by columnchromatography on silica gel with 20% ethyl acetate/PE to afford theproduct (900 mg, 3.47 mmol, 32% yield). LCMS: 260.1 (M+H) and 262.1(M+2+H), Rt 1.10 min Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm MobilePhase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of A131: To a stirred solution of A130 (250 mg, 0.96 mmol) inacetic acid (4.0 mL) was irradiated in microwave at 160° C. for 1 hourThe reaction mixture was cooled to room temperature and treated with 10%sodium bicarbonate solution (20 mL). The reaction mixture was extractedwith ethyl acetate (2×25 mL). The organic layer was washed with brine(2×20 mL), dried over Na₂SO₄ and concentrated. The crude product waspurified by column chromatography on silica gel with 35% EtOAc/PE toafford the product (110 mg, 0.45 mmol, 47% yield). LCMS: 242.1 (M+H) and244.1 (M+2+H), Rt 1.18 min Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μmMobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5mL/min.

Synthesis of Compound 87: To a stirred solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridine(250 mg, 0.75 mmol) and A131 (200 mg, 0.83 mmol) in 1,4-dioxane (5.0 mL)was added water (1.0 mL) and Cs₂CO₃ (491 mg, 1.51 mmol). Pd(dppf)Cl₂.DCM(65 mg, 0.08 mmol) was added to the reaction mixture under nitrogenatmosphere and heated at 80° C. for 16 hours The reaction mixture wascooled to room temperature, filtered through Celite and concentratedunder reduced pressure. The crude compound was purified by preparativeHPLC to afford the product (90 mg, 0.24 mmol, 32% yield) as a solid.Prep-HPLC method: Rt 8.37; Column: X-Bridge C-18 (150×19 mm), 5.0 μm;0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 4.18min, Column: X-Bridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFAin water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 367.1 (M+H),Rt 2.12 min, Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase:A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR(400 MHz, DMSO-d₆): δ 8.79-8.78 (m, 1H), 8.63 (d, 1H), 8.20 (dd, 1H),7.92 (dd, 1H), 7.81 (dd, 1H), 7.04 (d, 1H), 5.02 (s, 2H), 3.34 (s, 3H),1.82 (s, 6H).

Example 86:3-(ethoxydifluoromethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A134: To a stirred solution of1,1,1-trifluoro-2-methyl-propan-2-ol (5.0 g, 39.04 mmol) in THF (60.0mL) at 0° C. was added potassium tert-butoxide (6.57 g, 58.55 mmol) insmall portions. The reaction mixture was slowly warmed to roomtemperature and stirred for 15 min. 5-bromo-2-fluoro-pyridine (6.87 g,39.04 mmol) was added drop-wise to the reaction mixture and stirred for2 hours. The reaction mixture was cooled to 10° C. and treated with icewater (50 mL). The reaction mixture was extracted with ethyl acetate(2×60 mL). The organic layer was washed with brine (50 mL), dried overanhydrous Na₂SO₄ and concentrated. The crude compound was purified bycolumn chromatography on silica gel with 5% ethyl acetate/PE to affordthe product (2.3 g, 8.1 mmol, 20% yield). LCMS: 284.0 (M+H) and 286.0(M+2+H), Rt 2.96 min Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm MobilePhase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis A50: To a stirred solution of A134 (2.3 g, 8.1 mmol) andbis(pinacolato)diboron (2.26 g, 8.91 mmol) in 1,4-dioxane (40.0 mL) wasadded potassium acetate (1.59 g, 16.19 mmol). Pd(dppf)Cl₂.DCM (0.66 g,0.81 mmol) was added to the reaction mixture under nitrogen atmosphereand heated at 80° C. for 12 hours. The reaction mixture was cooled toroom temperature, filtered through Celite and concentrated under reducedpressure. The crude compound was purified by column chromatography onsilica gel with 5% ethyl acetate/PE to afford the product (1.8 g, 5.4mmol, 66% yield). LCMS: 332.1 (M+H), Rt 3.21 min Column: ATLANTIS dC-18(50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow Rate: 1.5 mL/min.

Synthesis of A53: To a stirred solution of A50 (1.2 g, 3.62 mmol) and6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (0.95g, 3.99 mmol) in 1,4-dioxane (20.0 mL) was added water (2.0 mL) andCs₂CO₃ (2.36 g, 7.25 mmol). Pd(dppf)Cl₂.DCM (0.3 g, 0.36 mmol) was addedto the reaction mixture under nitrogen atmosphere and heated at 80° C.for 12 hours. The reaction mixture was cooled to room temperature,filtered through Celite and concentrated under reduced pressure. Thecrude product was purified by column chromatography on silica gel with30% ethyl acetate/PE to afford the product (0.75 g, 1.84 mmol, 50%yield). LCMS: 408.0 (M+H), Rt 2.68 min Column: ZORBAX XDB C-18 (50×4.6mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN;Flow Rate: 1.5 mL/min.

Synthesis of Compound 88: To a stirred suspension of Cs₂CO₃ (1.43 g,4.41 mmol) in MeCN (3.0 mL) was added ethanol (0.52 mL, 8.83 mmol) atroom temperature and stirred for 15 min. To the reaction mixture A53(300 mg, 0.74 mmol) in MeCN (3.0 mL) was added dropwise and stirred for6 hours. The reaction mixture was treated with water (50 mL) andextracted with ethyl acetate (2×25 mL). The organic layer was washedwith brine (2×20 mL), dried over Na₂SO₄ and concentrated. The crudeproduct was purified by column chromatography on silica gel with 15%EtOAc/PE to afford the product (20 mg, 0.047 mmol, 6% yield) as a solid.HPLC: Rt 5.50 min, 98.5% Column: X-Bridge C8 (50×4.6) mm, 3.5 μm Mobilephase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min.LCMS: 418.1 (M+H), Rt 2.68 min, 97.8% Column: ZORBAX XDB C-18 (50×4.6mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN;Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆): δ 9.70 (d, 1H), 8.91(d, 2H), 8.46 (dd, 1H), 7.04 (d, 1H), 4.32 (q, 2H), 1.83 (s, 6H), 1.39(t, 3H).

Example 87: Synthesis of Compound 89

To a stirred solution of3-(chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine(146 mg, 0.38 mmol) in MeCN (5.0 mL) was added Cs₂CO₃ (751 mg, 2.3 mmol)and 2-methoxyethanol (0.38 mL, 4.8 mmol) at room temperature. Thereaction mixture was stirred for 3 h. The reaction mixture was treatedwater (15 mL) and extracted with ethyl acetate (2×15 mL). The organiclayer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated.The crude compound was purified by preparative HPLC to afford theproduct (15 mg, 0.03 mmol, 9% yield) as a solid. Prep-HPLC method: Rt11.3; Column: X-Bridge C8 (150×19 mm), 5.0 μm; 0.1% TFA inwater/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 4.69 min, Column:X-Bridge C8 (50×4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA in water, B:0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 420.0 (M+H), Rt 2.33 min,Column: X-Bridge C8 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% TFA inwater:ACN (95:5), B: 0.1% TFA in ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400MHz, DMSO-d₆): δ 9.72 (d, 1H), 8.93 (d, 1H), 8.89 (d, 1H), 8.44 (dd,1H), 7.21 (d, 1H), 5.10 (q, 2H), 4.39 (t, 2H), 3.72 (t, 2H), 3.32 (s,3H).

Example 88:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[rac-(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[rac-(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(500 mg, 1.21 mmol) and AgBF₄ (2.36 g, 12.15 mmol) in Methanol (5 mL)was stirred at 90° C. for 6 hours in a seal tube. After cooling to 25°C., the mixture was quenched with brine (20 mL), diluted with EtOAc (20mL) and filtered through Celite. The filtrate was extracted with EtOAc(20 mL×3), and the combined organic phase was washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 10% to 30%) togive the product (290 mg) as an oil. The impure product was purified byprep-HPLC (Xtimate C18 (150 mm×25 mm, 5 μm) A=H₂O (0.075% NH₄OH) andB=CH₃CN; 51-81% B over 11 minutes) to give the product (256.79 mg, 0.63mmol) as a solid. ¹H NMR (400 MHz CDCl₃) δ_(H)=9.52 (d, 1H), 8.50 (d,1H), 8.45 (d, 1H), 8.05 (dd, 1H), 5.95-5.85 (m, 1H), 3.98 (s, 3H), 1.60(d, 3H). LCMS Rt=1.33 min in 2 min chromatography, 10-80AB, MS ESIcalcd. for C₁₅H₁₂F₆N₅O₂ [M+H]+ 407.9, found 407.9.

Example 89:3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A123: A mixture of 2-bromo-5-chloro-pyrazine (1 g, 5.17mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(1.73 g, 5.17 mmol), Cs₂CO₃ (3.37 g, 10.34 mmol) and Pd(dppf)Cl₂ (567.41mg, 0.78 mmol) in 1,4-Dioxane (100 mL) and Water (10 mL) was stirred at55° C. under N₂ for 5 hours. From LCMS, desired MS was observed and nostarting material was remained. The solution was cooled to roomtemperature and concentrated to give a residue. To the residue was addedwater (50 mL), extracted with EtOAc (50 mL×2). The combined organicphase was washed with water (50 mL), brine (50 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by flash chromatography column on silicagel (EtOAc in PE=0% to 5%) to give the product (1.4 g, 4.35 mmol, 84%yield) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ_(H)=9.18 (s, 1H),8.91-8.74 (m, 2H), 8.46 (dd, 1H), 6.05-5.99 (m, 1H), 1.53 (d, 3H).

Synthesis of A124: A solution of2-chloro-5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazine(1.4 g, 4.35 mmol) and hydrazine (697.48 mg, 21.76 mmol) in MeCN (100mL) was stirred at 90° C. for 16 hours to give a colorless solution.After cooling to room temperature, the solution was concentrated to givea residue. To the residue was added water (50 mL), extracted with EtOAc(50 mL×2). The combined organic phase was washed with brine (50 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct (1.3 g, 4.10 mmol) as a solid which was used in the next stepdirectly. LCMS R_(t)=0.72 min in 1.5 min chromatography, 5-95AB, MS ESIcalcd. for C₁₂H₁₂F₄N₅O [M+H]⁺ 318.1, found 318.1.

Synthesis of A35: A mixture of[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]hydrazine(1.3 g, 4.1 mmol) and (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (2.99 g, 12.29 mmol) in Toluene (50 mL)was stirred at 110° C. for 3 days. After cooling to room temperature andconcentrated to give a residue. To the residue was added water (50 mL),extracted with EtOAc (50 mL×2). The combined organic phase was washedwith brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby chromatography flash column on silica gel (EtOAc in PE=0% to 10% to30%) to give the product (1.2 g, 2.91 mmol, 71% yield) as an oil. LCMSR_(t)=2.98 min in 4.0 min chromatography, 10-80AB, MS ESI calcd. forC₁₄H₉ClF₆N₅O [M+H]⁺ 412.0, found 411.9.

Synthesis of Compound 6B: A mixture of3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine(1.2 g, 2.91 mmol) and AgOTf (7.49 g, 29.15 mmol) in MeCN (24 mL) andMethanol (24 mL) was stirred at 90° C. for 5 days. Then EtOAc (50 mL)and brine (50 mL) was added to the mixture, some solid was observed andthe mixture was filtered through Celite. The filtrate was separated andthe aqueous layer was extracted with EtOAc (50 mL). The combined organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by chromatographyflash on silica gel (EtOAc in PE=10% to 30% to 50%) and then by Prep-TLC(PE:EA=2:1) to give the product (160 mg, 389.5 μmol, 13% yield) as asolid. ¹H NMR (CDCl₃+D₂O, 400 MHz) δ_(H)=9.52 (s, 1H), 8.50 (s, 1H),8.45 (s, 1H), 8.04 (d, 1H), 5.93-5.87 (m, 1H), 3.98 (s, 3H), 1.60 (d,3H). LCMS R_(t)=1.30 min in 2.0 min chromatography, 10-80AB, MS ESIcalcd. for C₁₅H₁₂F₆N₅O₂ [M+H]⁺ 408.1, found 407.9.

Example 90: 2-chloro-5-hydrazineylpyrazine

Synthesis of A12: To a stirred solution of 2,5-dichloropyrazine (20.0 g,134.2 mmol) in ethanol (200 mL) was added hydrazine hydrate (20.16 g,402.74 mmol) and heated to 80° C. for 12 hours. The reaction mixture wascooled to room temperature and treated with ice water. The precipitatedsolid was filtered, washed with water and dried to get the product (16.0g) as a solid.

Example 91:2-(3,3-difluorocyclobutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Synthesis of A108: To a stirred solution of 3,3-difluorocyclobutanol(1.2 g, 11.1 mmol) and 5-bromo-2-fluoro-pyridine (1.5 g, 8.52 mmol) in1,4-dioxane (15 mL) at 0° C. was added KO^(t)Bu (1.9 g, 17.05 mmol) insmall portions. The reaction mixture was slowly warmed to roomtemperature and stirred for 6 hours. The reaction mixture was treatedwith ice water (30 mL) and extracted with ethyl acetate (2×30 mL). Theorganic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄and concentrated to afford the product (1.6 g) which was used for thenext step without further purification. LCMS: 264.0 (M+H) and 266.0(M+2+H), Rt 2.63 min Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm MobilePhase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of A106: To a stirred solution of5-bromo-2-(3,3-difluorocyclobutoxy)pyridine (1.6 g, 6.06 mmol) andbis(pinacolato)diboron (2.0 g, 7.88 mmol) in 1,4-dioxane (32.0 mL) wasadded potassium acetate (1.78 g, 18.2 mmol). Pd(dppf)Cl₂.DCM (0.49 g,0.61 mmol) was added to the reaction mixture under nitrogen atmosphereand heated at 80° C. for 12 hours. The reaction mixture was cooled toroom temperature, filtered through Celite and concentrated under reducedpressure. The crude compound was purified by column chromatography onsilica gel with 5% ethyl acetate/PE to afford the product (1.82 g, 5.8mmol, 96% yield). LCMS: 312.2 (M+H), Rt 2.87 min Column: ZORBAX XDB C-18(50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow Rate: 1.5 mL/min.

Example 92:[5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine

Synthesis of A42: A mixture of 2-bromo-5-chloro-pyrazine (2 g, 10.34mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(3.61 g, 10.34 mmol), Cs₂CO₃ (6.74 g, 20.68 mmol) and Pd(dppf)Cl₂ (1.13g, 1.55 mmol) in 1,4-Dioxane (80 mL) and Water (8 mL) was stirred at 55°C. under N₂ for 5 hours. The mixture was cooled to room temperature andconcentrated to give a residue. To the residue was added water (50 mL)and extracted with EtOAc (50 mL×2). The combined organic phase waswashed with water (50 mL), brine (50 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography column on silica gel (EtOAc inPE=0% to 5% to 10%) to give the product (2.3 g, 5.45 mmol) as a solid.¹H NMR (400 MHz, CDCl₃) δ_(H)=8.77 (d, 1H), 8.64 (d, 1H), 8.53 (d, 1H),8.05 (dd, 1H), 1.88 (s, 6H). LCMS R_(t)=0.96 min in 1.5 minchromatography, MS ESI calcd. for C₁₃H₁₁ClF₄N₃O [M+H]⁺ 336.0, found335.9.

Synthesis of A28: A solution of2-chloro-5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazine(2.3 g, 6.85 mmol) and hydrazine (2.20 g, 68.52 mmol) in MeCN (50 mL)was stirred at 90° C. under N₂ for 16 hours to give a solution. Aftercooling to room temperature, the solution was concentrated to give aresidue. To the residue was added water (50 mL) and extracted with EtOAc(50 mL×2). The combined organic phase was washed with brine (50 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated to give theproduct (2.1 g, 6.34 mmol, 92.52% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.42 (d, 2H), 8.29 (s, 1H), 7.94 (d, 1H), 6.12 (s, 1H),3.92 (s, 2H), 1.84 (s, 6H). LCMS R_(t)=0.77 min in 1.5 minchromatography, MS ESI calcd. for C₁₃H₁₄F₄N₅O [M+H]⁺ 332.1, found 331.9.

Example 93:3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A22: A mixture of 2-bromo-5-chloro-pyrazine (800 mg, 4.14mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine(1642.99 mg, 4.55 mmol), Cs₂CO₃ (4042.64 mg, 12.41 mmol), Pd(dppf)Cl₂(60.52 mg, 0.08 mmol) in 1,4-dioxane (12 mL) and H₂O (4 mL) was stirredat 50° C. for 8 hours. After cooling to room temperature, the reactionmixture was concentrated to remove solvent, diluted with water (20 mL),and extracted with EtOAc (20 mL×2). The combined organic phase waswashed with brine (40 mL), dried over Na₂SO₄ and concentrated to give acrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 10%) to give the product as a solid, whichwas confirmed by LCMS R_(t)=1.01 min in 1.5 min chromatography, MS ESIcalcd. for C₁₄H₁₁ClF₄N₃O [M+H]⁺ 348.1, found 347.9.

Synthesis of A23: A mixture of2-chloro-5-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazine(0.8 g, 2.3 mmol) and hydrazine (0.74 g, 23.01 mmol) in MeCN (20 mL) washeated to 90° C. and stirred for 16 hours. After cooling to roomtemperature, the reaction mixture was concentrated to give crude productas a solid. LCMS R_(t)=1.04 min in 2.0 min chromatography, MS ESI calcd.for C₁₄H₁₄F₄N₅O [M+H]⁺ 344.1, found 344.0.

Synthesis of A24: To a mixture of[5-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazin-2-yl]hydrazine(0.6 g, 1.75 mmol) in toluene (40 mL) was added(2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (0.64 g,2.62 mmol). The reaction mixture was stirred at 110° C. for 96 hours.After cooling to room temperature, the reaction mixture was concentratedto give a residue. The residue was diluted with sat.NaHCO₃ (50 mL), andextracted with EtOAc (50 mL×2). The combined organic phase was washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated to givea residue. The residue was purified by flash column on silica gel (EtOAcin PE=0% to 20%) to give the product as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=9.60 (d, 1H), 8.51 (d, 1H), 8.45 (s, 1H), 8.06 (dd, 1H), 2.87-2.97(m, 2H), 2.73-2.81 (m, 2H), 1.91-2.04 (m, 2H).

Example 94.3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A140: A mixture of 2-bromo-5-chloro-pyrazine (2 g, 10.34mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(3.12 g, 9.31 mmol), Pd(dppf)Cl₂ (1.13 g, 1.55 mmol) and Cs₂CO₃ (6.74 g,20.68 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was stirred underN₂ at 50° C. for 5 hours. After cooling to room temperature, the mixturewas diluted with EtOAc (10 mL), filtered with silica gel, eluted withEtOAc (20 mL) and concentrated to give the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 20%) to give the product (2500 mg, 7.21 mmol, 70% yield) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.77 (d, 1H), 8.64 (d, 1H), 8.53(d, 1H), 8.08 (dd, 1H), 6.00-5.83 (m, 1H), 1.59 (d, 3H).

Synthesis of A141: A mixture of2-chloro-5-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazine(2 g, 6.22 mmol) and hydrazine (1.99 g, 62.18 mmol) in MeCN (20 mL) washeated to 90° C. and stirred for 16 hours. After cooling to roomtemperature, the reaction mixture was concentrated to remove most of theMeCN, then diluted with H₂O (100 mL). The mixture was extracted withEtOAc (150 mL×2). The combined organic phase was washed with brine (100mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give thecrude product (2000 mg, 6.30 mmol) as an oil. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=8.62 (d, 1H), 8.58 (d, 1H), 8.29-8.24 (m, 2H), 8.19 (s, 1H),6.05-5.92 (m, 1H), 4.37 (brs, 2H), 1.51 (d, 3H).

Synthesis of A31: A solution of[5-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]hydrazine(250 mg, 0.79 mmol) and (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (0.21 mL, 1.18 mmol) in toluene (20 mL)was stirred at 110° C. for 7 days. The mixture was concentrated. Theresidue was diluted with EtOAc (30 mL), basified with saturated NaHCO₃to pH 7-8 and washed with H₂O (30 mL×2) and brine (20 mL). The combinedorganic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=5% to 20% to 50%) to give the product (240 mg,0.58 mmol, 74% yield) as an oil. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=9.77(d, 1H), 9.13 (d, 1H), 8.83 (d, 1H), 8.65 (dd, 1H), 6.10-5.95 (m, 1H),1.55 (d, 3H).

Example 95:3-[bromo(difluoro)methyl]-6-[6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A145: To a solution of (2R)-1,1,1-trifluoropropan-2-ol (139g, 1.22 mol) in THF (1570 mL) was added NaH (73.11 g, 1.83 mol, 60% inoil) at 0° C. over 1 hour. The mixture was stirred at 0° C. for 30 mins.Then 5-bromo-2-fluoro-pyridine (193.01 g, 1.10 mol) was added and themixture was stirred at 30° C. for 4 hours. The mixture was quenched withsat. NH₄Cl (1000 mL). The mixture was extracted with EtOAc (1000 mL).The combined organic phase was washed with brine (500 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated to give the product (240 g,888.72 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.18 (d, 1H), 7.71(dd, 1H), 6.74 (d, 1H), 5.78-5.64 (m, 1H), 1.49 (d, 3H).

Synthesis of A146: A mixture of5-bromo-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (240 g, 888.7mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(270.82 g, 1.07 mol), KOAc (174.44 g, 1.78 mol) and Pd(dppf)Cl₂ (26.01g, 35.55 mmol) in 1,4-dioxane (2000 mL) was stirred at 90° C. for 12hours under N₂. The mixture was cooled then concentrated and the crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0 to 1% to 3% to 10%) to give the product (200 g, 630.7 mmol, 71%yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.51 (d, 1H), 7.98 (dd,1H), 6.79 (d, 1H), 5.90-5.80 (m, 1H), 1.49 (d, 3H), 1.35 (s, 12H).

Synthesis of A147: A mixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methy1-ethoxy]pyridine (200 g, 630.7 mmol), 2-bromo-5-chloro-pyrazine (122 g,630.7 mmol), Pd(dppf)Cl₂ (46.15 g, 63.07 mmol) and Cs₂CO₃ (513.7 g, 1.58mol) in 1,4-dioxane (2000 mL) and water (500 mL) was stirred at 50° C.for 2 hours under N₂. After cooling to 25° C., the mixture was separatedand the organic phase was concentrated to remove most of dioxane. Theresidue was poured into water (1 L) and the mixture was extracted withEtOAc (800 mL×2). The combined organic phase was washed with water (500mL) and brine (500 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 1% to 3% to 20%) to give the product (122g, 401.75 mmol, 64% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.77-8.73 (m, 2H), 8.63 (d, 1H), 8.26 (dd, 1H), 6.96 (d, 1H),5.93-5.82 (m, 1H), 1.54 (d, 3H).

Synthesis of A148: To a solution of2-chloro-5-[6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazine(122 g, 401.75 mmol) in MeCN (1000 mL) was added hydrazine (128.76 g,4.02 mol) at 25° C. The mixture was stirred at 90° C. for 16 hours.After cooling to 25° C., the reaction was poured into water (2 L) andthe solid was collected by filtration and washed with water (500 mL×2).The solid was dissolved in EtOAc (1500 mL) and the mixture was washedwith brine (500 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product (120 g, 401 mmol) as a solid.LCMS Rt=0.96 min in 2 min chromatography, 10-80AB, MS ESI calcd. ForC₁₂H₁₃F₃N₅O [M+H]⁺ 300.1, found 299.9.

Synthesis of A149: To a solution of 2-bromo-2,2-difluoro-acetic acid (91g, 520.21 mmol) in THF (1000 mL) was added one drop DMF and (COCl)₂(52.82 mL, 624.25 mmol). The mixture was stirred at 20° C. for 30 mins.Then[5-[6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]hydrazine(120 g, 401 mmol) was added to the solution. The mixture was stirred at20° C. for 1 hour. The mixture was poured in to water (2 L) and theaqueous layer was extracted with EtOAc (2 L×2). The combined organicphase was washed with brine (1L×2), dried over anhydrous Na₂SO₄,filtered and concentrated to give the product (180 g, 293.6 mmol) as asolid.

Synthesis of A122: To a solution of2-bromo-2,2-difluoro-N′-[5-[6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]acetohydrazide(180 g, 293.6 mmol) in toluene (1500 mL) was added TsOH (5.18 g, 30.07mmol). The mixture was stirred at 125° C. for 16 hours. After cooling toroom temperature, the mixture was poured in to water (1.5 L) and theaqueous layer was extracted with EtOAc (1.5 L×2). The combined organicphase was washed with brine (500 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 20%) to give theproduct (55 g, 125.57 mmol, 31% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=9.59 (d, 1H), 8.76 (d, 1H), 8.41 (d, 1H), 8.25 (dd, 1H),7.01 (d, 1H), 5.96-5.80 (m, 1H), 1.56 (d, 3H).

Example 96:3-[bromo(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A150: A mixture of 2-bromo-5-chloro-3-methyl-pyrazine (2.47g, 11.91 mmol),3-fluoro-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(3.9 g, 11.64 mmol), Cs₂CO₃ (7.76 g, 23.81 mmol) and Pd(dppf)Cl₂ (1.31g, 1.79 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was stirred at50° C. under N₂ for 2 hours. After cooling to room temperature, water(20 mL) and EtOAc (30 mL) were added and the mixture was filteredthrough Celite. After separating, the organic phase was washed withbrine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=0% to 3%) to give the product (2.57 g, 7.65 mmol, 64%yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.51 (s, 1H), 8.18 (s,1H), 7.71 (d, 1H), 5.95-5.82 (m, 1H), 2.69 (s, 3H), 1.59 (d, 3H).

Synthesis of A151: A solution of5-chloro-2-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-methyl-pyrazine(2.57 g, 7.66 mmol) and hydrazine hydrate (5.75 g, 114.84 mmol) in MeCN(25 mL) was stirred at 90° C. for 12 hours. After cooling to roomtemperature, the solution was concentrated. Water (20 mL) was added andthe aqueous layer was extracted with EtOAc (30 mL×2). The combinedorganic phase was washed with brine (30 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give the crude product (2.3 g, 6.9mmol) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=8.18 (d, 1H), 8.09 (s,1H), 8.06 (s, 1H), 7.96 (dd, 1H), 6.07-5.90 (m, 1H), 4.33 (s, 2H), 2.41(s, 3H), 1.52 (d, 3H).

Synthesis of A152: A mixture of[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-6-methyl-pyrazin-2-yl]hydrazine(1.3 g, 3.92 mmol) and 2-bromo-2,2-difluoro-acetyl chloride (1.1 g, 5.69mmol) in DCM (15 mL) was stirred at 20° C. for 0.5 hour. Water (20 mL)was added and the aqueous layer was extracted with EtOAc (30 mL×2). Thecombined organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to50%) to give the product (1.4 g, 2.86 mmol, 73% yield) as a solid. ¹HNMR (400 MHz, DMSO-d₆) δ_(H)=11.39 (s, 1H), 9.40 (s, 1H), 8.24 (d, 1H),8.04 (dd, 1H), 7.97 (s, 1H), 6.08-5.95 (m, 1H), 2.47 (s, 3H), 1.53 (d,3H).

Synthesis of A101: To a mixture of2-bromo-2,2-difluoro-N′-[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-6-methyl-pyrazin-2-yl]acetohydrazide(1.44 g, 2.89 mmol) and 2-Methoxypyridine (0.77 mL, 7.23 mmol) in DCM(15 mL) was added Tf₂O (897.7 mg, 3.18 mmol). The resulting mixture wasstirred at 20° C. for 0.5 hour. Water (20 mL) was added and the aqueouslayer was extracted with EtOAc (20 mL×2). The combined organic phase waswashed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 30% to 50%) to give the product (390 mg,711.9 μmol, 24% yield) as an oil. LCMS R_(t)=1.32 min in 2.0 minchromatography, 10-80AB, MS ESI calcd. for C₁₅H₁₁BrF₆N₅O [M+H]⁺ 472.0,found 471.8.

Example 97:3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of A19-a: A mixture of 2-bromo-5-chloro-pyrazine (2 g, 10.34mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(3983.83 mg, 12.41 mmol), Pd(dppf)Cl₂ (1134.83 mg, 1.55 mmol) and Cs₂CO₃(6737.32 mg, 20.68 mmol) in 1,4-dioxane (30 mL) and water (3 mL) wasstirred at 60° C. for 5 hours under N₂. The mixture was filtered throughCelite, and eluted with EtOAc (30 mL×2). The filtrate was concentratedand the crude product was purified by flash chromatography on silica gel(EtOAc in PE=0% to 20%) to give the product (2500 mg, 7.83 mmol, 77%yield) as a solid. LCMS Rt=0.88 min in 1.5 min chromatography, 5-95AB,MS ESI calcd. C₁₁H₇ClF₄N₃O [M+H]⁺ 308.0, found 308.1.

Synthesis of A20-a: A mixture of2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (2.5g, 8.13 mmol) and hydrazine (2.6 g, 81.27 mmol) in CH₃CN (60 mL) wasstirred at 85° C. for 4 days. After cooling to room temperature, thereaction was quenched with sat.NH₄Cl (50 mL) and the mixture wasextracted with EtOAc (40 mL×2). The combined organic phase was washedwith brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product (2400 mg, 5.79 mmol) as a solid.LCMS Rt=0.69 min in 1.5 min chromatography, 5-95AB, MS ESI calcd.C₁₁H₁₀F₄N₅O [M+H]⁺ 304.1, found 304.1.

Synthesis of A114: A mixture of[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine(2.4 g, 7.92 mmol) and(2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (5.77 g,23.75 mmol) in toluene (50 mL) was stirred at 120° C. for 7 days. Aftercooling to room temperature, the reaction was quenched with sat.NaHCO₃(50 mL) and the mixture was extracted with EtOAc (50 mL×2). The combinedorganic phase was washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The crude product was purified byflash chromatography on silica gel (EtOAc in PE=0% to 30%) to give theproduct (2500 mg, 5.13 mmol, 65% yield) as an oil. LCMS Rt=2.70 min in 4min chromatography, 10-80AB, MS ESI calcd. C₁₃H₇ClF₆N₅O [M+H]⁺ 398.0,found 398.0.

Details for the synthesis of certain intermediates and startingmaterials may be found in PCT/US2017/063533 and PCT/US2018/000224, thecontents of which are incorporated herein by reference.

Example 98. Efficacy of Exemplary Compounds in the Modulation of LateSodium Current (INaL)

Functional characterization of exemplary compounds to modulate INaLexpressed by the NaV1.6 voltage-gated sodium channel was accomplishedusing the PatchXpress™ high throughput electrophysiology platform(Molecular Devices, Sunnyvale, Calif.). HEK-293 cells expressingrecombinant, human NaV1.6 (hNaV1.6) were grown in DMEM/high-glucoseDulbecco's modified, 10% FBS, 2 mM sodium pyruvate, 10 mM HEPES and 400μg/mL G418. Cells were grown to 50% 80% confluency prior to harvesting.Trypsinized cells were washed, allowed to recover for 1 hour and thenresuspended in extracellular recording solution at a concentration of1×106 cells/ml. The onboard liquid handling facility of the PatchXpresswas used for dispensing cells and applying test compounds. NaV latecurrents were evoked by the application of 300 nM ATX-II. INaL wasevoked by depolarizing pulses to 0 mV for 200 ms from a non-inactivatingholding potential (e.g., −120 mV) at a frequency of 0.1 Hz. INaLamplitude and stability were determined by analyzing the mean currentamplitude over the final 20 ms of the test pulse. Following steady stateblock with exemplary compounds (e.g., as described herein), a Na+ freesolution containing an impermeant cation (e.g., Choline or NDMG) wasadded to confirm the identify of the sodium current. Percentsteady-state inhibition of INaL was calculated as:[(INaL_compound)/(INaL_control)]*100, where INaL_compound and INaLcontrol represent INaL recorded in the presence or absence of compound,respectively.

Results from this assay relating to percent inhibition of INaL athNaV1.6 (measured using a procedure similar to described above but usingHEK-293 cells expressing recombinant, human NaV 1.6 (h NaV 1.6) at 1 μMare summarized in Table 1 below. Similarly, results from an assayrelating to percent inhibition of INaL at hNaV1.2 (measured using aprocedure similar to described above but using HEK-293 cells expressingrecombinant, human NaV 1.2 (h NaV 1.2) at 1 μM are summarized in Table 2below. In this table, “A” indicates inhibition of less than 30%; “B”indicates inhibition of between about 30% to about 70%; and “C”indicates inhibition of greater than 70%.

TABLE 1 No. NaV 1.6 Assay Data  1 C  2 C  3 C  4 C  5 C  6A C  6B C  7 C 8 C  9 C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20 C 21 C 22C 23 C 24 C 25 C 26 C 27 C 28 C 29 A 30 C 31 A 32 C 33 C 34 C 35 A 36 C37 C 38 B 39 A 40 A 41 C 42 C 43 B 44 B 45 C 46 B 47 C 48 C 49 C 50 C 51C 52 B 53 C 56 C 57 C 58 C 59 C 60 B 61 B 62 C 63 C 64 C 65 B 66 C 67 C68 C 69 B 70 A 71 A 72 A 73 C 74 C 75 C 76 C 77 C 78 C 79 C 81 C 82 C 83B 84 C 85 C 86 C 87 B 88 C 89 B

TABLE 2 No. NaV 1.2 Assay Data 16 C 10 C 53 C 56 C 59 C 62 C

Example 99. Crystallinity Analyses of Compounds by X-Ray PowderDiffractometer and Differential Scanning Calorimetry

X-ray powder diffraction (XRPD) data were collected using a Bruker D8Advance powder diffractometer. The samples were irradiated with copperK-alpha X-rays (λ=1.54179 Å) with the generator operating at 40 kV/40mA. The samples were scanned in continuous mode from 3° to 40° (2θ) witha sample rotation speed of 15 rpm and a scanning rate of 10°/min.

Differential scanning calorimetry (DSC) data were collected using a TAQ2000. For each sample analyzed, approximately 1 mg of sample was placedinside a hermetically sealed aluminum pan, containing a pinhole, andheated at a rate of 10° C./min from 25° C. to 300° C.

FIGS. 1A-9A show XRPD patterns of compounds 10, 62, 6B, 56, 3, 11, 53,59, and 48 raw materials, respectively. FIGS. 1B-9B show DSC ofcompounds 10, 62, 6B, 56, 3, 11, 53, 59, and 48 respectively. Tables3-11 show XRPD prominent peaks corresponding to FIGS. 1A-9A,respectively.

TABLE 3 Compound 10 - XRPD prominent peaks corresponding to FIG. 1A2-Theta I % 9.3 100 12.0 23 13.0 8.3 16.1 54.6 17.7 15.5 18.8 98.5 19.28.8 21.1 56.2 21.4 59.5 21.6 45.9 21.9 10.2 22.6 38.9 23.9 31.6 25.2 1725.4 13.9 26.0 28.6 26.4 30.6 27.8 6.3 28.5 9.8 29.4 17.7 29.6 8.2 30.324.6 32.0 3.4 33.1 4.6 33.8 1.9 35.6 4.1 36.2 4.8 39.4 6.1

TABLE 4 Compound 62 - XRPD prominent peaks corresponding to FIG. 2A2-Theta I % 6.9 100 7.5 0.6 11.2 6.4 13.7 4.3 13.9 25.5 16.5 27.2 17.44.2 18.1 7 19.1 4.5 19.5 25.5 20.8 41 26.8 1.6 29.1 0.9 29.3 7 33.2 3.635.0 3.5 36.2 3.1 38.7 1.3

TABLE 5 Compound 6B - XRPD prominent peaks corresponding to FIG. 3A2-Theta I % 7.2 52.7 10.4 7.3 12.8 11.1 14.1 15.6 14.4 41.4 15.5 8 15.912.3 16.2 10.2 16.7 58.2 17.9 28.8 18.5 23.9 19.0 100 20.4 58.9 20.827.4 21.8 12.8 23.2 41.6 24.0 24.8 24.5 18.4 24.9 6.9 25.3 9.5 25.7 48.526.5 12.1 28.0 38.8 28.8 9.7 29.2 13 29.6 21.7 30.3 7.8 31.8 10.6 32.46.4

TABLE 6 Compound 56 - XRPD prominent peaks corresponding to FIG. 4A2-Theta I % 7.3 100 13.7 4.7 14.5 34.8 16.0 1.9 17.9 15.7 19.0 16.3 20.37.6 21.9 20.8 24.7 6 25.4 5.7 28.9 4 32.5 1.9 36.8 2.2

TABLE 7 Compound 3 - XRPD prominent peaks corresponding to FIG. 5A2-Theta I % 3.2 5.9 8.4 13.4 9.0 4.9 10.7 30.5 12.3 31.5 12.6 57 14.75.6 14.9 20.3 15.8 37 16.6 26 16.8 24.3 18.1 2.2 18.3 7.9 18.6 100 19.62.8 20.6 13.2 21.0 24.5 21.4 8.3 22.4 7.4 22.6 36.4 23.8 7.6 24.7 7.525.3 23.3 26.9 5.9 27.2 6.6 27.9 4.2 28.1 9.3 29.5 6.2 29.7 5.2 31.1 2.732.8 2.8 33.2 2.5 35.9 2.8 37.5 5.8

TABLE 8 Compound 11 - XPRD prominent peaks corresponding to FIG. 6A2-Theta I % 5.8 100 9.9 4.1 11.6 13.7 12.0 10.5 14.5 15.3 15.3 16.1 16.04.9 16.8 8.6 17.5 8.6 18.7 6.7 19.1 9.2 19.7 19.7 20.7 6.8 21.0 33.121.7 2.9 22.4 9.8 23.4 5.7 24.2 19.5 26.4 14.8 27.4 22.9 27.9 3.1 29.58.5 29.7 4.3 32.1 12 32.6 4.9 34.3 2.7 35.4 13.8 35.9 2.7 37.6 3.2

TABLE 9 Compound 53 - XRPD prominent peaks corresponding to FIG. 7A2-Theta I % 7.3 53.8 10.8 10.6 12.3 4.7 12.6 13 13.8 10.9 14.6 6.4 15.05.2 16.6 51 17.8 10.9 18.4 100 19.5 8.1 19.7 4.3 20.3 18.5 20.6 4.7 21.29.9 21.6 4.7 22.0 5.7 23.4 7.1 23.6 4 24.3 38.5 25.3 6.1 25.9 7.3 26.611.1 27.0 3 28.0 17.1 29.5 4.3 31.2 6.8 32.7 2 33.0 2.2 37.3 3.2

TABLE 10 Compound 59 - XRPD prominent peaks corresponding to FIG. 8A2-Theta I % 6.9 100 9.5 6 11.2 28.8 13.6 13.9 13.9 19.4 15.0 10 16.472.1 16.9 6.3 17.4 46.6 18.0 33.3 19.1 28.5 19.5 56.5 20.8 30.4 21.2 8.222.2 1.7 22.5 3.6 22.6 3.4 23.3 3.7 24.5 5.2 24.8 10.1 26.3 3.1 26.714.3 26.9 8.1 27.6 8.4 28.4 3.4 28.7 3 29.0 5.5 29.3 10.5 30.1 3.4 33.29 35.0 2 36.1 3.3 38.7 2.9

TABLE 11 Compound 48 - XRPD prominent peaks corresponding to FIG. 9A2-Theta I % 7.3 23.6 9.9 97.6 11.0 7.3 12.3 74 13.8 26.2 14.1 70.7 14.611.8 15.2 7.8 15.7 21 16.5 42.1 17.2 35.2 17.4 16.3 18.8 44.7 19.5 16.119.8 100 20.3 28.4 20.7 68.8 21.5 11.1 22.3 17 22.5 10.6 23.7 74 24.863.6 26.1 10.6 27.7 51.5 28.7 18.2 29.1 48.2 29.7 11.1 30.1 7.8 31.211.8 31.7 12.3 33.5 5.4 35.7 8.7

Example 100. In Vitro Assay Data Peak and Ramp

Functional characterization of exemplary compounds to modulate INaexpressed by various human isoforms and disease-causing mutantvoltage-gated sodium channels was accomplished using the PatchXpresshigh throughput electrophysiology platform (Molecular Devices,Sunnyvale, Calif.). HEK-293 cells expressing a recombinant, human NaV1.Xsodium channel (either hNaV1.6-WT, hNaV1.6-R223G, hNaV1.6-N984K,hNaV1.6-N1768D, hNaV1.1-WT, hNaV1.2-WT, hNaV1.5-WT, hNaV1.7-WT, orhNaV1.8-WT) were grown in DMEM/high-glucose Dulbecco's modified, 10%FBS, 2 mM sodium pyruvate, 10 mM HEPES and 400 μg/mL G418. Cells weregrown to 50% 80% confluency prior to harvesting. Trypsinized cells werewashed, allowed to recover for 1 hour and then resuspended inextracellular recording solution at a concentration of 1×10⁶ cells/ml.The onboard liquid handling facility of the PatchXpress was used fordispensing cells and applying test compounds. INa amplitude andstability were determined by analyzing the peak current amplitude.

Voltage Step Activated Sodium Current

Peak INa was evoked by depolarizing steps to 0 mV for 20 ms from aholding potential which evoked half-inactivation (e.g., −60 mV) at afrequency of 0.1 Hz. The voltage of half-inactivation was determined foreach cell using a 5 sec prepulse to membrane potentials between −120 mVand −20 mV followed immediately by a voltage step to a fully activatingmembrane voltage (e.g., 0 mV). Following steady state block withexemplary compounds (e.g., as described herein), the degree ofinhibition was measured using the average of three consecutive voltagesteps. Percent steady-state inhibition of INa was calculated as:[(INa_compound)/(INa_control)]*100, where INa_compound and INa_controlrepresent INa recorded in the presence or absence of compound,respectively.

Results from this assay relating to percent inhibition measured at 1 aresummarized in Table 18 below. In this table, “A” indicates inhibitionbetween less than 0% to 50% and “B” indicates inhibition of greater than50% and N/A indicates the compound was not tested.

Voltage Ramp Activated Sodium Current

The Nav1.6 mutant channels (hNaV1.6-R223G, hNaV1.6-N984K,hNaV1.6-N1768D) express an enhanced sodium current in response to a rampvoltage depolarization when compared to the wild-type hNaV1.6-WT. Thisenhanced, depolarizing ramp current is thought to contribute to enhancedneuronal excitability. The degree of block with exemplary compounds(e.g., as described herein) was measured using a +600 mv/sec voltageramp from −100 mV to +20 mV. The ramp current was defined as the area ofthe current measured between −55 mV and +15 mV. Following steady stateblock with exemplary compounds (e.g., as described herein) at 1 μM, aNa⁺ free solution containing an impermeant cation (e.g., Choline orNMDG) was added for determination of the baseline current level foroffline subtraction. Percent inhibition of enhanced ramp current wascalculated as (compound−baseline)/(control−baseline)*100, where controlrepresents the ramp current recorded in the absence of compound. Resultsfrom this assay are summarized in Table 19 below. In this table, “A”indicates inhibition between less than 0% to 50% and “B” indicatesinhibition of greater than 50% and N/A indicates the compound was nottested.

TABLE 18 hNav1.1 hNav1.2 hNav1.5 hNav1.6 hNav1.7 hNav1.8 Peak Peak PeakPeak Peak Peak Compound INa INa INa INa INa INa   6B B B B B B B 3 B N/AB B B B 10 B A B B B B 11 B N/A B B B B 48 N/A N/A B B B B 53 B A B B BB 56 B B B B B B 59 B B B B B B 62 B B B B B B

TABLE 19 hNav1.6-R223G hNav1.6-N984K hNav1.6-N1768D Compound Ramp INaRamp INa Ramp INa  6B B B B  3 B B B 10 B A B 11 A B B 48 A A B 53 A A B56 A B B 59 B B B 62 A B B

Example 101. Mouse MES Protocol

Methods:

Male CD-1 mice, weighing 25-35 g were assessed in the MaximalElectroshock induced Seizure (IVIES) assay. Briefly, mice were dosedwith compound (n=12/group) according to the dosing parameters in Table20 and the latency to induce tonic hind limb extension followingtransauricular electrical stimulation (50 Hz, 50 mA, 0.8 sec duration,pulse width of 10 ms) was recorded up to 60 seconds post stimulus. Meanlatency to tonic extension data for all compounds are presented in Table21.

TABLE 20 Mouse MES dosing parameters. Dose Pre-treatment time CompoundVehicle route (min) 10 35% HPCD PO 30  6B 35% HPCD PO 120 53 35% HPCD PO30 62 35% HPCD PO 30 48 35% HPCD PO 30  3 35% HPCD PO 30Results:

TABLE 21 Mean latency to tonic hind limb extension in the MES assay Meanlatency to tonic extension (s) Compound 1 mg/kg 3 mg/kg 10 mg/kg 10 7.936.3 55.2  6B 17.3 50.5 53 36.4 60 60 62 17.6 46.1 48 42.5 60  3 60 60

Example 102. Bile-Metabolite Study

Bile samples are collected (0-4, 4-8, and 8-24 hours post dose) fromthree male Sprague-Dawley rats following a single intravenous (IV) bolusadministration of test compounds, for example, compound 3, 10, 15, 56,62, or 65, administered at 1 mg/kg to bile duct cannulated rats. Thebile samples are pooled in a volume proportional manner to give one 0-24hour sample. This sample is quenched with two volumes of acetonitrile,vortexed, centrifuged and the supernatant transferred to a 96-well plateand partially dried under nitrogen.

The 0-24 hour bile sample for each rat is analyzed by ultra-highperformance liquid chromatography coupled to high resolution massspectrometry (UPLC-HRMS) and the full scan data processed using manualand automated methods including, for example, Masslynx or Metabolynx, toidentify the presence of both expected and unanticipated metabolites.The UPLC-HRMS full scan data are used to define the masses of the parentand metabolites. A separate UPLC-HRMS/MS acquisition is conducted togenerate product ion spectra for each metabolite. The metabolitestructures are proposed by comparison of the metabolite high resolutionproduct ion spectra with the high resolution product ion spectrum of thetest compound. Bile samples from rats receiving compound treatment willdisplay altered metabolite levels and metabolic pathway activation.

Example 103: Evaluation of Effects on Seizures and Survival in theSCN2A^(Q54) Transgenic Mouse Model

To evaluate the effect on seizures and survival in a mouse model ofincreased persistent sodium current, the compounds disclosed in thepresent application, for example, compound 3, 6B, 10, 11, 53, 56, 59, or62, may be evaluated in the SCN2A^(Q54) transgenic mouse model (KearneyJ. A. et al. A gain-of-function mutation in the sodium channel geneScn2a results in seizures and behavioral abnormalities. Neuroscience,102(2), 307-317 (2001)). SCN2A^(Q54) transgenic mice express a transgenewith three mutations in the sodium channel NaV1.2 (G879Q, A880Q, L881Q),which leads to an increase in neuronal persistent sodium current.Increased persistent sodium current in these mice is correlated with anepilepsy phenotype and premature death. The compounds (for example,compound 3, 6B, 10, 11, 53, 56, 59, or 62) may be dosed systemically(e.g. by oral gavage, by subcutaneous or intraperitoneal injection, etc)once or twice daily to achieve appropriate plasma levels. In someinstances, the compound may be provided in the chow fed ad libitum. Forevaluation of acute anticonvulsant effects of compound seizures may berecorded by continuous video recording and/or electroencephalography(EEG) using indwelling electrodes. Anticonvulsant activity may beevaluated by comparing the number of spontaneous behavioral seizures(tonic deviation of the head and body accompanied by forelimb clonus) orspontaneous seizures recorded using EEG, during a 30 60 minutepretreatment period with the number of seizures occurring during a 30 60minute post treatment period. Administration of the compound may resultin a decreased number of seizures compared to baseline (pretreatment).To evaluate compound effects on survival, compounds may be dosedchronically for several weeks, starting, for example, at 3 weeks of ageuntil, for example, 16 weeks of age. Administration of compound mayresult in reduction of the number of premature deaths. For detailedmethods see Anderson L. L. et al. Antiepileptic activity of preferentialinhibitors of persistent sodium current. Epilepsia, 55(8), 1274-1283(2014).

Example 104: Evaluation of Effects on Seizures and Survival inTransgenic Mouse Models with Pathogenic Gain of Function Mutations inSCN2A and SCN8A (Scn2a (R1882Q) Mouse Model and Scn8a^(N1768D/+) MouseModel)

To evaluate the effect on seizures and survival in mouse models ofepileptic encephalopathy, mouse models carrying pathogenic gain offunction mutations may be used, for example the Scn2a (R1882Q) mousemodel, carrying a gain of function mutation in NaV1.2 (Petrou et al.Antisense oligonucleotide therapy for SCN2A gain-of-function epilepsies(Abst. 1.466), American Epilepsy Society. 2018) and theSC118a^(N1768D/+) mouse model carrying a gain of function mutation inNaV1.6 (Wagnon J. L. et al. Convulsive seizures and SUDEP in a mousmouse model of SCN8A epileptic encephalopathy. Human Molecular Genetics,24(2), 506-515 (2015)). The compounds disclosed in the presentapplication (for example, compound 3, 6B, 10, 11, 53, 56, 59, or 62) maybe dosed systemically (e.g. by oral gavage, by subcutaneous orintraperitoneal injection, etc) once or twice daily to achieveappropriate plasma levels. In some instances, the compound may beprovided in the chow fed ad libitum. As the phenotype of these modelscan be severe, treatment may begin with a very young age (e.g. beforeweaning and as early as postnatal day 5) or by treatment of the dam toachieve appropriate plasma levels in nursing pups. For evaluation ofcompound effects on spontaneous seizures, seizures may be recorded overone or more days by continuous video recording and/or EEG recording andcounted by a reviewer of the video and/or EEG data. The number ofspontaneous seizures per hour after treatment may be compared to thenumber of spontaneous seizures in vehicle treated animals over the sametime period. Administration of the compound may result in a decreasednumber of seizures per hour compared to vehicle treated animals. Toevaluate compound effects on survival, compounds may be dosedchronically for several weeks until for example at least 50% of animalshave died in the control group. Dosing start may be for example as earlyas postnatal day 10 in the SCN2A R1882Q model, postnatal day 30-40 inScn8a^(N1768D/+) mice (heterozygous N1768D mice), or postnatal day 5 inScn8a^(D/D) mice (homozygous N1768d mice). Administration of compoundmay result in reduction of the number of premature deaths compared tovehicle treated mice. For detailed methods see e.g. Baker E. M. et al.The novel sodium channel modulator GS-458967 (GS967) in an effectivetreatment in a mouse model of SCN8A encephalopathy. Epilepsia. 59(6),1166-76 (2018).

Example 105: Evaluation of Effects on Seizures and Survival in a MouseModel of Dravet Syndrome

To evaluate the effect on seizures and survival in a mouse model ofDravet syndrome, the compounds disclosed in the present application, forexample, compound 3, 6B, 10, 11, 53, 56, 59, or 62, may be evaluated inthe Scn1a^(+/−) mouse model. The compounds (for example, compound 3, 6B,10, 11, 53, 56, 59, or 62) may be dosed systemically (e.g. by oralgavage, by subcutaneous or intraperitoneal injection, etc) once or twicedaily to achieve appropriate plasma levels. In some instances, compoundmay be provided in the chow fed ad libitum. As the phenotype of thesemodels can be severe, treatment might begin with treatment of pupsbefore weaning or treatment of the dam to achieve appropriate plasmalevels in nursing pups. To increase the severity of the phenotype ofthis mouse model, Scn1a^(+/−) mice might be exposed to elevatedtemperature for a short period of time of up to 42 degrees Celsius toinduce a short hyperthermia-induced seizure around the time of weaning.For evaluation of compound effects on spontaneous seizures, seizures maybe recorded for example for one or more days by continuous videorecording and/or EEG recording and counted by a reviewer of the videoand/or EEG data. The number of spontaneous seizures per hour aftercompound treatment may be compared to the number of spontaneous seizuresper hour in vehicle treated animals over the same time period.Administration of the compound may result in a decreased number ofseizures per hour compared to vehicle treated animals. To evaluatecompound effects on survival, compounds may be dosed chronically forseveral weeks until at least 50% of animals have died in the controlgroup. Dosing would start for example on postnatal day 18.Administration of compound may result in reduction of the number ofpremature deaths compared to vehicle treated mice. For detailed methodssee Anderson L. L. et al. Unexpected efficacy of a novel sodium channelmodulator in Dravel syndrome. Sci. Rep. 10: 7(1), 1682 (2017).

Example 106: Evaluation of Effects on Seizures, Survival and OtherEndpoints in Transgenic Mice of Epileptic Encephalopathy Such as a KCNT1Mouse Model Carrying the Mouse Equivalent of a Human Pathogenic Mutation(e.g. P924L)

Homozygous mice carrying the mouse equivalent of the human P924Lmutation (P905L), exhibit spontaneous seizures, interictal discharges,impaired nesting behavior, and a shortened life span (Burbano L. et alCharacterization of a Novel Knock-in Mouse Model of KCNT1 EpilepticEncephalopathy (P2.273). Neurology April 2018, 90 (15 Supplement)P2.273). The compounds disclosed in the present application, forexample, compound 3, 6B, 10, 11, 53, 56, 59, or 62 may be dosedsystemically (e.g. by oral gavage, by subcutaneous or intraperitonealinjection, etc.) once or twice daily to achieve appropriate plasmalevels. In some instances, the compound may be provided in the chow fedad libitum. As the phenotype of these models can be severe, treatmentmay begin with treatment of pups before weaning or treatment of the damto achieve appropriate plasma levels in nursing pups. For evaluation ofcompound effects on spontaneous seizures, seizures may be recorded forexample for one or more days by continuous video recording and/or EEGrecording as described in the previous example. The number ofspontaneous seizures after treatment may be compared to the number ofspontaneous seizures in vehicle treated animals over the same timeperiod. Administration of the compound may result in a decreased numberof seizures compared to vehicle treated animals. For evaluation ofcompound effects on interictal discharges, interictal discharges may berecorded by EEG over 1 or more days and counted by a reviewer. Thenumber of interictal discharges per hour after treatment may be comparedto the number of interictal discharges per hour in vehicle treatedanimals over the same time period. Administration of the compound mayresult in a decrease in the number of interictal discharge compared tovehicle treated animals. For evaluation of compound effects on nestbuilding behavior, mice may be presented with nest building material(e.g. tissue paper) and ability to build nests compared to vehicletreated animal will be assessed. Administration of the compound mayresult in increased ability to build nests compared to vehicle treatedanimals. To evaluate compound effects on survival, compounds may bedosed chronically for several weeks until at least 50% of animals havedied in the control group. Dosing may start, for example, on postnatalday 18. Administration of the compound may result in reduction of thenumber of premature deaths compared to vehicle treated mice.

Example 107: Post-Surgical Pain

The analgesic efficacy of the compounds disclosed in the presentapplication, for example, compound 3, 6B, 10, 11, 53, 56, 59, or 62, maybe assessed in the post-incision model in rats. Rats may be anesthetizedand receive an incision in one hindpaw. The following day, rats may beadministered test compound (e.g., compound 3, 6B, 10, 11, 53, 56, 59, or62) by a systemic route of administration (e.g., oral gavage,subcutaneous injection, intravenous, etc.) to achieve appropriate plasmaexposure. Between 30 and 120 min later, mechanical allodynia may beassessed using the Up-down method with von Frey hairs (Chaplan, S. R.,Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. Quantitativeassessment of tactile allodynia in the rat paw. J Neurosci Meth 53,55-63 (1994). Rats may be stimulated with the hair in the middle of theseries (for example, 2.0 g) and consequent stimuli may be presented inconsecutive order, either ascending or descending. A paw withdrawalresponse to the hair may result in presentation of the next weakerstimulus; absence of a paw withdrawal response may result inpresentation of the next stronger stimulus. Administration of thecompound may result in increased threshold for von Frey hair stimulationto induce paw withdrawal i.e. decreased mechanical allodynia.

Example 108: Neuropathic Pain

The analgesic efficacy of the compounds of the present application, forexample, compound 3, 6B, 10, 11, 53, 56, 59, or 62, may be assessedusing preclinical models of neuropathic pain in rats. Neurophysiologicalmeasures will be recorded in the spinal cord (dorsal horn) and brain(ventral posterolateral nucleus (VPL) of the thalamus) of anesthetizedrats. The effects of systemic administration of compounds (e.g. bysubcutaneous injection, intravenous etc.) that achieve appropriateplasma exposure will be assessed in spinal nerve ligated and shamoperated rats, as recently described for oxcarbazepine (Kim, S. & Chung,J. An experimental model for peripheral neuropathy produced by segmentalspinal nerve ligation in the rat. Pain 50, 355-363 (1992)). Spinal nerveligation (SNL) of the left L5 and L6 spinal nerves may be performed toinduce a model of unilateral peripheral neuropathic pain; sham rats willundergo all steps of this surgery, apart from the nerve isolation andligation (Patel, R., Kucharczyk, M., Montagut-Bordas, C., Lockwood, S. &Dickenson, A. H. Neuropathy following spinal nerve injury sharesfeatures with the irritable nociceptor phenotype: A back-translationalstudy of oxcarbazepine. Eur J Pain 23, 183-197 (2019)). After recoveryfrom the SNL or sham surgery, thalamic recordings may be obtained byimplanting parylene-coated tungsten electrodes into the right ventralposterolateral nucleus (VPL) of the thalamus. Spontaneous neuronalactivity and neuronal activity evoked using natural stimuli, forexample, dynamic brushing, mechanical pressure, cold or heat, tostimulate the receptive field may be recorded from sham and SNL rats atbaseline and at various time points (e.g. 10-120 min) afteradministration of compounds. Extracellular recordings from deep dorsalhorn laminae neurons may be made in anesthetized sham and SNL rats whichhave had a laminectomy to access L4-L6 segments of the spinal cord.Spontaneous neuronal activity and activity evoked by electrical stimuli(typically 2 ms pulses, 0.5 Hz) or natural stimuli (as described above)may be recorded at baseline and at various time points (e.g. 10-120 min)after administration of compounds. Spinal nerve ligation may result inexaggerated responses in the thalamus and dorsal horn to some modalitiesof stimulation (e.g. brushing, mechanical pressure, cold and heat).Administration of the compound may result in attenuation of theseexaggerated responses in the thalamus and/or dorsal horn followingstimulation compared to vehicle treated spinal nerve ligated rats.Furthermore, in a separate study, mechanical allodynia may be assessedin rats after spinal nerve ligation surgery. 1-2 weeks after surgery,mechanical allodynia will be assessed using the Up-Down method with vonFrey hairs¹. Rats may then be dosed chronically with systemic compound,for example compound 3, 6B, 10, 11, 53, 56, 59, or 62, (e.g. by oralgavage, subcutaneous injection, etc.) to achieve appropriate plasmaexposure and mechanical allodynia may be assessed using the Up-Downmethod after the acute administration of the compound and subsequentlyat least once per week for 2 weeks. Administration of the compound mayresult in increased threshold for von Frey hair stimulation to inducepaw withdrawal, i.e. decreased mechanical allodynia.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or subrange within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

The invention claimed is:
 1. The compound:

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and thecompound:

or a pharmaceutically acceptable salt thereof.
 3. The compound:


4. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and the compound:


5. A crystalline form of the compound:

wherein the crystalline form is characterized by an X-ray powderdiffraction pattern comprising X-ray power diffraction peaks at thefollowing diffraction angles (° 2θ): 9.3°±0.2°, 18.8°±0.2°, and21.4°±0.2° (2θ).
 6. The crystalline form of claim 5, wherein thecrystalline form is further characterized by an X-ray powder diffractionpattern comprising additional X-ray powder diffraction peaks at thefollowing diffraction angles (° 2θ): 16.1°±0.2°, 21.1°±0.2°, and21.6°±0.2° (2θ).
 7. The crystalline form of claim 5, wherein thecrystalline form is further characterized by an X-ray powder diffractionpattern comprising additional X-ray powder diffraction peaks at thefollowing diffraction angles (° 2θ): 16.1°±0.2°, 21.1°±0.2°, 21.6°±0.2°,22.6°±0.2°, 23.9°±0.2°, 26.0°±0.2°, and 26.4°±0.2° (2θ).
 8. Thecrystalline form of claim 5, wherein the crystalline form ischaracterized by an X-ray powder diffraction pattern as shown in FIG.1A.
 9. The crystalline form of claim 5, wherein the X-ray powderdiffraction pattern is obtained using Cu Kα radiation.
 10. Thecrystalline form of claim 5, wherein the crystalline form has a meltingpoint onset as determined by differential scanning calorimetry at 122°C.
 11. The crystalline form of claim 5, wherein the crystalline form hasa differential scanning calorimetry curve as shown in FIG. 1B.
 12. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and the crystalline form of claim
 5. 13. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and thecrystalline form of claim
 6. 14. A pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the crystalline form of claim7.
 15. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and the crystalline form of claim
 8. 16. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and the crystalline form of claim
 9. 17. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and thecrystalline form of claim
 10. 18. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and the crystallineform of claim 11.